Film formulations containing dexmedetomidine and methods of producing them

ABSTRACT

Disclosed herein is a self-supporting, dissolvable, film containing dexmedetomidine or a pharmaceutically acceptable salt thereof. The film is administered orally to treat various conditions, particularly agitation, by transmucosal delivery of the active agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/103,013, filed Nov. 24, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/931,630, filed Jul. 17, 2020, which is acontinuation of U.S. patent application Ser. No. 16/453,679, filed Jun.26, 2019 (U.S. Pat. No. 10,792,246, issued Oct. 6, 2020), and claims thebenefit of priority to U.S. Provisional Application Nos. 62/690,407,filed Jun. 27, 2018; 62/693,726, filed Jul. 3, 2018; 62/767,422, filedNov. 14, 2018; 62/787,649, filed Jan. 2, 2019; 62/798,842, filed Jan.30, 2019; and 62/849,747, filed May 17, 2019; each of which is hereinincorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

Disclosed herein is a self-supporting, dissolvable, film containingdexmedetomidine or a pharmaceutically acceptable salt thereof. The filmis administered orally to treat various conditions, particularlyagitation, by transmucosal delivery of the active agent. The film isformulated to produce a rapid onset of action without the significantsedation normally associated with the administration of dexmedetomidine.

BACKGROUND OF THE INVENTION

On Dec. 17, 1999, the U.S. Food and Drug Administration approved adexmedetomidine product, PRECEDEX®, formulated as an intravenoussolution for continuous infusion, and indicated as a sedative agent forinitially intubated and mechanically ventilated patients duringtreatment in an intensive care setting. PRECEDEX® was later approved asa sedative agent for non-intubated patients prior to and/or duringsurgical and other procedures.

In addition to its use as a sedative, dexmedetomidine also has analgesicand anti-agitation properties. However, to date, it has not beenpossible to develop a formulation comprising dexmedetomidine for use asan anti-agitation agent. For example, PRECEDEX® is not a suitableanti-agitation agent for the following reasons: it can presently only beadministered in an enrolled healthcare facility to patients; the abilityto titrate the dose to suit individual patient requirements ischallenging; self-administration is generally impractical sincePRECEDEX® is administered as an injection; and its significant sedativeproperties can be undesirable in many settings to treat agitatedsubjects.

A continuing, unmet need exists for non-addictive anti-agitationmedicines. A dexmedetomidine-based medicine that could beself-administered, e.g. orally, to produce rapid relief from agitationwithout significant sedation would be highly valuable addition toagitation treatment options. However, administering dexmedetomidineorally to provide fast relief from agitation is challenging. Forexample, sublingual tablets have a tendency to be swallowed beforecomplete dissolution and trans-mucosal delivery, leading to wastage ofactive substance due to hepatic first pass metabolism. As a result,sublingual tablets may not achieve therapeutic levels of dexmedetomidinein the blood plasma. Oral sprays, especially for sublingual delivery,also have deficiencies, such as dose inaccuracy, swallowing of drug, theneed for frequent dosing, patient non-compliance, and cost of goods. Inaddition, significant cardiovascular side-effects have been shown tooccur in human subjects treated with dexmedetomidine hydrochloride whenadministered as a sublingual spray (see International Patent ApplicationPublication No. WO 2010/132882). WO 2010/132882 teaches than, whendexmedetomidine hydrochloride was administered sublingually oradministered by IV, a significant number of subjects experiencedhypotension post-administration together with an undesirably high levelof sedation. Hypotension was observed at a sublingual dose of 100micrograms dexmedetomidine and, to a lesser extent, at 50 micrograms.These, and other, limitations taught by existing dexmedetomidineformulations have disincentivized the development of an oraldexmedetomidine formulation to treat agitation. However, the inventorsof this application have now surprisingly discovered a new oral filmformulation which can be administered to treat agitation without theaforementioned limitations.

SUMMARY OF THE INVENTION

The disclosure provides a self-supporting, dissolvable, film comprisingdexmedetomidine or a pharmaceutically acceptable salt thereof, one ormore water-soluble polymers, and, optionally, one or morepharmaceutically acceptable carriers. The film is formulated to releasedexmedetomidine rapidly, enabling dexmedetomidine to be absorbedtransmucosally to provide effective anti-agitation relief for patientswithin minutes, without concomitant significant sedation.

In one embodiment, the disclosure provides a pharmaceutical filmcomposition suitable for sublingual administration, comprising, orconsisting essentially of, a therapeutically effective amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof, a polymercomponent consisting of one or more water-soluble polymers; and,optionally, one or more pharmaceutically acceptable carriers.

In one embodiment, the disclosure provides film formulations comprisinga polymer-based film substrate (e.g. a drug-free polymer matrix film)containing on the surface of the substrate dexmedetomidine or apharmaceutically acceptable salt thereof. Dexmedetomidine or apharmaceutically acceptable salt thereof may be conveniently applied tothe surface of the film substrate as part of a composition alsocomprising a liquid carrier, and optionally a polymer component and/orone or more additional pharmaceutically acceptable carriers (hereinafterreferred to as the “dexmedetomidine composition”).

The dexmedetomidine composition may, in one aspect of this disclosure,be applied to the film substrate as a single droplet or multipledroplets at one or more specific substrate locations, or alternativelythrough discrete deposition (e.g. micro-deposition) of thedexmedetomidine composition at isolated locations on a common placebofilm.

In another aspect, the disclosure provides film formulations comprisinga polymer-based film substrate (e.g. a drug-free polymer matrix film)onto the surface of which is stenciled the dexmedetomidine compositionat one or more discrete locations.

In another aspect, the dexmedetomidine composition may be present on thesurface of the film substrate, after drying, as one or more discretelines. The line(s) may be applied using either a direct deposition orstenciling method.

In some embodiments, the substrate is formed as a continuous web offilm, which may be cut into smaller individual films followingdeposition of the individual units of the dexmedetomidine compositionand drying.

One advantage of such films is the ability to deposit a highconcentration of dexmedetomidine onto the surface of the “placebo”substrate for rapid trans-mucosal delivery of dexmedetomidine. Anotheradvantage is that the use of individually formed doses limits variationof the active ingredient between dosage units. Particularly in the casewhen the surface of the film substrate is stenciled with thedexmedetomidine composition, advantages include the ability to deliverreadily an appropriate thickness of dexmedetomidine composition onto thesurface of the film. Still another advantage of the deposition methodincludes the ability to incorporate a combination of dexmedetomidine ora pharmaceutically acceptable salt thereof and one or more additionalactives into a single unit dose, even if the active ingredients wouldotherwise be incompatible with one another, through discrete depositionof those active ingredients at separate locations on the substrate. Yetanother advantage is the avoidance of yield losses associated withconventional dissolvable film production processes. Because theformulations used to create the film generally contain relativelyexpensive pharmaceuticals, these yield losses represent a significantcost.

In a further embodiment, the disclosure provides film formulationscomprising dexmedetomidine or a pharmaceutically acceptable salt thereofdisposed within a polymer matrix, e.g. wherein dexmedetomidine or apharmaceutically acceptable salt thereof is substantially uniformallydistributed throughout the film.

The disclosure also provides processes for preparing films of thepresent disclosure. In one process, a film is produced in whichdexmedetomidine or a pharmaceutically acceptable salt thereof isdisposed (e.g. substantially uniformally distributed) within apolymer-based film. In another process, a film is produced in whichdexmedetomidine or a pharmaceutically acceptable salt thereof is presenton the surface of a polymer-based film substrate.

Also disclosed herein, as embodiments of the disclosure, are solutionsor suspensions containing dexmedetomidine or a pharmaceuticallyacceptable salt thereof suitable for depositing onto the surface of thepolymer-based film substrate (i.e. the “dexmedetomidine compositions”).

The disclosure also provides methods of treating agitation in a human byadministering the films disclosed herein. Various conditions requiringanti-agitation therapy may be treated by sublingual administration of afilm disclosed herein, including agitation associated withneurodegenerative and neuropsychiatric diseases, particularly innon-institutionalized patients. The treatment provides effectivenon-coercive anti-agitation therapy with adequate safety profile, andfavorable tolerability, thus mitigating the risk of high bloodpressure/respiratory depression.

The administration of a film composition of the present disclosure to apatient suffering from agitation substantially reduces the risk ofviolence and injury to the patient and others by preventing thecondition from worsening and/or limiting the duration and severity ofthe agitation outburst. The film compositions of the present disclosureare especially useful in managing acute agitation events. They can alsobe safely administered either in a clinical facility or outside of aclinical facility.

These and other features, advantages and objects of the variousembodiments will be better understood with reference to the followingdescription of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: shows a cross-sectional (side) view and area (top) view of anexemplary monolithic drug-containing matrix film disclosed herein.

FIG. 2: shows a cross-sectional (side) view and area (top) view of anexemplary micro-deposited matrix film disclosed herein.

FIG. 3 compares the diffusion of dexmedetomidine film formulationsdisclosed herein (represented by Formulations 1 to 7 and Formulation 11of Example 1 hereinafter) through an oral cell culture membrane versusthe diffusion of PRECEDEX®.

FIG. 4 shows the mean dexmedetomidine plasma log concentration vs. timefor dose levels 10, 20 and 40 mcg of dexmedetomdine sublingual film(Semi-log scale). Error bars represent 1 standard deviation.

FIG. 5A: depicts individual dexmedetomidine concentration-time profilesfor all subjects by dose after administration of dexmedetomidinesublingual film (10 mcg) Semi-log Scale. Dexmedetomidine sublingual filmis exemplified in Example 1, Formulation 12.

FIG. 5B: depicts individual dexmedetomidine concentration-time profilesfor all subjects by dose after administration of dexmedetomidinesublingual film (20 mcg) Semi-log Scale. Dexmedetomidine sublingual filmis exemplified in Example 1, Formulation 12.

FIG. 5C: depicts individual dexmedetomidine concentration-time profilesfor all subjects by dose after administration of dexmedetomidinesublingual film (40 mcg) Semi-log Scale. Dexmedetomidine sublingual filmis exemplified in Example 1, Formulation 12.

FIG. 6: depicts mean VAS/S score vs. Nominal Time after administrationof dexmedetomidine sublingual film (10, 20, 40 mcg) and Placebo.Dexmedetomidine sublingual film is exemplified in Example 1, Formulation12.

FIG. 7: depicts standing Systolic BP vs Nominal Time afteradministration of dexmedetomidine sublingual film (10, 20, 40 mcg) andPlacebo. Dexmedetomidine sublingual film is exemplified in Example 1,Formulation 12.

FIG. 8: depicts supine Systolic BP. vs Nominal Time after administrationof dexmedetomidine sublingual film 10 mcg, 20 mcg and 40 mcg andPlacebo. Dexmedetomidine sublingual film is exemplified in Example 1,Formulation 12.

FIG. 9: depicts standing Diastolic BP vs Nominal Time afteradministration of dexmedetomidine sublingual film 10 mcg, 20 mcg and 40mcg and Placebo. Dexmedetomidine sublingual film is exemplified inExample 1, Formulation 12.

FIG. 10: depicts supine Diastolic BP vs Nominal Time afteradministration of dexmedetomidine sublingual film 10 mcg, 20 mcg and 40mcg and Placebo. Dexmedetomidine sublingual film is exemplified inExample 1, Formulation 12.

FIG. 11: depicts pulse Rate vs Nominal Time after administration ofdexmedetomidine sublingual film 10 mcg, 20 mcg and 40 mcg and Placebo.Dexmedetomidine sublingual film is exemplified in Example 1, Formulation12.

FIG. 12: depicts the percentage of schizophrenic patients achievingRASS−1 in the treatment arm (IV dexmedetomidine hydrochloride treatedgroup) versus placebo group.

FIG. 13: depicts the reduction in PEC score with time in schizophrenicpatients in the treatment arm (IV dexmedetomidine hydrochloride treatedgroup) versus placebo group.

FIG. 14: depicts the maximum doses of IV dexmedetomidine hydrochloridereceived by schizophrenic patients for the treatment of agitation.

FIG. 15: depicts the total intravenous dose of dexmedetomidinehydrochloride received by schizophrenic patients for the treatment ofagitation.

FIG. 16: depicts the mean Plasma concentration (pg/ml) vs actual time inschizophrenic patients treated with dexmedetomidine hydrochloride.

FIG. 17: depicts the mean (±SD) dexmedetomidine plasmaconcentration-time, sorted by dose level (Linear Scale)

FIG. 18: depicts the mean (±SD) dexmedetomidine plasmaconcentration-time, sorted by dose level (Semi-log Scale)

FIG. 19: depicts the mean (±SD) change in PEC Score from baseline inschizophrenic patients treated with dexmedetomidine hydrochloride (120mcg) versus pooled placebo group

FIG. 20: depicts the mean (±SD) percent change in PEC Score frombaseline in schizophrenic patients treated with dexmedetomidinehydrochloride (120 mcg) versus pooled placebo group.

DETAILED DESCRIPTION

Abbreviations:

AD: Alzheimer disease;

AUC: Area under the curve;

AUC_(last): area under the curve, calculated to the last observable timepoint;

C_(max): maximum plasma concentration;

CT: Computed tomography;

DPBS: Dulbeccos phosphate-buffered saline;

DLB: Dementia with Lewy bodies;

FTD: Fronto temporal disease;

HPC: Hydroxypropyl cellulose;

IPD: In-patient Departments;

MW: Molecular weight;

MRT_(last): Mean residence time, calculated to the last observable timepoint;

MM: Magnetic resonance imaging;

mm: Millimeter;

OPD: Out-Patient Department;

PANSS: Positive and Negative Syndrome Scale

PEC: PANSS Excitement Component

PEO: Polyethylene oxide;

PD: Parkinson disease;

PTSD: Post-traumatic stress disorder

RASS: Richmond Agitation Sedation Scale

TEER: Transepitheleal electrical resistance;

T_(max): Time of maximum plasma concentration

Wt %: Weight percentage

Definitions

It will be understood that the term “film” herein includes thin films,sheets and wafers, in any shape, including rectangular, square, or otherdesired shape. The film may be of any desired thickness and size, suchthat it can be conveniently placed sub-lingually in the patient. Forexample, the film may be a relatively thin film having a thickness offrom about 20 micrometers to about 200 micrometers, or may be a somewhatthicker film having a thickness of from about 20 micrometers to about1000 micrometers. In certain embodiments, the film may be even thicker,e.g., having a thickness greater than about 30 millimeters.

As used herein, the phrase “water-soluble polymer” refers to (i) apolymer that is at least partially soluble in water, and desirably fullyor predominantly soluble in water, and/or (ii) a polymer that absorbswater. Polymers that absorb water are referred to herein aswater-swellable polymers. Suitable polymers include polymers that arewater-soluble at room temperature and other temperatures, such astemperatures exceeding room temperature. Moreover, suitable polymersinclude polymers that are water-soluble at pressures less thanatmospheric pressure. Desirably, water-swellable polymers have at leasta 20 percent by weight water uptake, e.g. a 25 or greater percent byweight water uptake. In one embodiment, film formulations comprise oneor more water-soluble polymers that promote the dissolution of the filmupon contact with oral mucosal fluids.

The terms “formulation” and “composition” are used interchangeably,except where otherwise clearly intended to have different meanings.

The term “pharmaceutically acceptable carrier” refers to apharmacologically inert substance to be used as a carrier. As usedherein, the phrase “carrier” and “excipients” are used interchangeably,except where otherwise clearly intended to have different meanings.

As used herein, the term “monolithic” in the context of a filmcomposition, refers to a single layer polymer film as a “placebo” filmmatrix or a drug-containing film matrix. In some aspects, a monolithicfilm is used as a drug-free film matrix intermediate product in thepreparation of a drug micro-deposited matrix film composition.

As used here, the term “dosage form” refers to a film composition in aportion that delivers a single dose, in a single administration, to asubject.

The term “self-supporting” means the films herein maintain structuralintegrity upon handling without the need for a backing layer. Someflexibility in the film is contemplated and may be desirable.

The term “dissolvable” means the films herein are readily disintegrated,e.g. at least within about 20 minutes, following administration to theoral mucosa. Disintegration is achieved by saliva and/or other aqueousmaterials on the mucosal surface.

The term “without significant sedation” and the like means that thepatient experiences a level of sedation not greater than Level 3 on theRamsay Sedation Scale. Level 3 means sedated, but responds to commands.In certain aspects, the dexmedetomidine may be dosed to achieve aRichmond Agitation Sedation Scale (RASS) of −1 (“light sedation”).

As used herein, “about” means plus or minus 10% of the indicatednumerical value.

As used herein, the phrase “disposed within a polymer matrix” means thatdexmedetomidine or a pharmaceutically acceptable salt thereof isincorporated directly into the polymer solution prior to the formationof the solid polymer matrix film composition.

As used herein, the phrase “deposited on the surface of a polymermatrix” means that dexmedetomidine or a pharmaceutically acceptable saltthereof is formulated as liquid composition separate from thepreparation of the solid polymer matrix, and deposited onto the solidpolymer, e.g. as one or more micro-deposits, where it dries. The driedproduct is sometimes referred to herein as the “micro-deposited matrixfilm”. The drug liquid formulation may be in any form, including as asolution, emulsion, suspension, or dispersion.

Film Compositions:

The present disclosure provides pharmaceutical film compositionscomprising, or consisting essentially of, dexmedetomidine or apharmaceutically acceptable salt thereof, as an active agent, a polymercomponent, and optionally one or more pharmaceutically acceptablecarriers. The disclosed film compositions have desirably functionalattributes for sublingual administration. In particular, thedisintegration time of the film compositions is such that the oromucosaldelivery of dexmedetomidine or a pharmaceutically acceptable saltthereof is effective to rapidly treat agitation in a subject. Forexample, the film compositions may conveniently disintegrate completelysublingually in about 15 seconds to about 180 seconds, for example,about 30 seconds to about 180 seconds, including about 120 seconds.Disintegration times in about this time-frame assist in optimalsub-lingual delivery of the drug and in optimal onset of drug effect.

Active Agent

Dexmedetomidine has the IUPAC name (+)4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. As themonohydrochloride salt, it is predominantly used as a medication for thesedation of patients during treatment in an intensive care setting or tosedate patients prior to and/or during surgical and other procedures.Such medication is currently sold under the registered trade name“PRECEDEX”.

Pharmaceutically acceptable salts of dexmedetomidine that may be used inthe film compositions disclosed herein include generally any suitablesalt that has been or may be approved by the US FDA or other appropriateforeign or domestic agency for administration to a human. Non-limitingexamples of suitable pharmaceutically acceptable salts include salts ofinorganic acids such as hydrochloric, hydrobromic, nitric, carbonic,monohydrocarbonic, phosphoric, monohydrogen phosphoric, dihydrogenphosphoric, sulfuric, hydrogen sulfuric, and hydroiodic acid. Otherexamples include salts derived from non-toxic organic acids, includingacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-toluenesulfonic, citric, tartaric, and methanesulfonic acids, orcombinations of these acid salts. Exemplary salts includedexmedetomidine hydrochloride, dexmedetomidine hydrobromide,dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidinephosphate, dexmedetomidine nitrate, dexmedetomidine formate,dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidinemalate, dexmedetomidine benzoate, dexmedetomidine salicylate,dexmedetomidine ascorbate or the like. In other embodiments, deuteratedforms of dexmedetomidine or a pharmaceutically acceptable salt thereofmay be included in the film composition.

Dexmedetomidine or a pharmaceutically acceptable salt thereof mayconveniently comprise about 0.01% to about 50%, e.g. about 0.05% toabout 30%, e.g. about 0.05% to about 20%, e.g. about 0.05% to about 3%weight/weight (w/w) based on the total weight of a film composition on adry weight basis. However, it will be appreciated that, when the filmcomposition is a micro-deposited matrix film, the w/w % ofdexmedetomidine or a pharmaceutically acceptable salt may vary from theafore-mentioned percentages depending on the total dimensions (andtherefore total weight) of each unit dose of film.

In one aspect, dexmedetomidine or a pharmaceutically acceptable saltthereof may be present at about 0.05 mcg to about 3 mcg for each 100 mcgof unit dose total weight of film composition.

The film formulations disclosed herein comprise dexmedetomidine or apharmaceutically acceptable salt thereof either (i) disposed within apolymer matrix or (ii) deposited on the surface of a polymer matrix,e.g., on the surface of a “placebo” film.

Further, dexmedetomidine or a pharmaceutically acceptable salt thereofmay be incorporated as part of a film composition in a taste-maskedform. In this embodiment, particles of drug may be coated or granulatedwith a taste-masking agent, for example a polymer, oil, or wax.

Polymer Component

The polymer component consists of one or more water-soluble polymers.The polymer component is present in the film composition in a sufficientamount to ensure disintegration of the subsequently formed film matrixis achieved in the oral mucosa within a suitable timeframe, for example,allowing the film matrix to disintegrate completely sublingually inabout 15 seconds to about 180 seconds, for example, about 30 seconds toabout 180 seconds, including about 120 seconds. The present disclosureprovides film compositions comprising at least one water-soluble polymerthat yield films of sufficient film strength (i.e. self-supporting) andrapid disintegration profiles. In one aspect of the disclosure, thepolymer component consists of a single water-soluble polymer. In anotheraspect, the polymer component consists of two or more water-solublepolymers, including two or more of the same water-soluble polymershaving different molecular weights.

When present in one or more droplets of the dexmedetomidine compositionwhich is deposited onto the surface of the polymer substrate, thepolymer component may, for example, consist of the water-soluble polymerhydroxypropyl cellulose, although different water-soluble polymers arealso contemplated as described hereinafter under the definition “firstwater-soluble polymer” and “second water soluble polymer”. For example,the polymer component may consist of one, two or three hydroxypropylcelluloses having different molecular weights. The molecular weights ofthe different hydroxypropyl celluloses may conveniently range from (i)less than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000daltons) (ii) about 90,000 daltons to about 200,000 daltons and (iii)about 200,000 daltons to about 500,000 daltons. The two or morehydroxypropyl celluloses may be mixed in any suitable ratio to achievethe desired droplet viscosity. The viscosity of the dexmedetomidinecomposition solution or suspension can be measured using a Brookfieldviscometer with a small sample adapter at a temperature of 25° C. andmay range from about 5 cps to about 3700 cps. For example, it may rangefrom about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6cps to about 100 cps or about 6 cps to about 50 cps. In one aspect ofthe present disclosure, the viscosity of the dexmedetomidine compositionsolution or suspension is from about 6 cps to about 20 cps at 25° C. anda shear rate of about 7 (1/s).

When present in a monolithic (i.e. placebo or drug-containing) film, thepolymer component may, for example, consist of one water soluble polymeror two different water-soluble polymers. When two differentwater-soluble polymers are present, one of the water-soluble polymersmay include the same polymer but present in the polymer component as acombination of different molecular weights. For example, the polymercomponent may consist of one, two or three hydroxypropyl celluloseshaving different molecular weights, although different water-solublepolymers are also contemplated as described hereinafter under thedefinition “first water-soluble polymer” and “second water solublepolymer” such as polyethylene oxide. The molecular weights of thedifferent hydroxypropyl celluloses may conveniently range from (i) about5000 daltons to about 49000 daltons (ii) about 90000 daltons to about200000 daltons and (iii) about 200,000 daltons to about 500,000 daltons(e.g. about 300000 daltons to about 450000 daltons). The two or morehydroxypropyl celluloses (e.g. low and high molecular weighthydroxypropyl celluloses) may be mixed in any suitable ratio to achievethe desired film properties.

When present in a monolithic (i.e. placebo or drug-containing) film ormicro-deposited film matrix composition, the polymer component mayconveniently consist of one or more water-soluble polymers having amolecular weight less than about 60,000 daltons (e.g. about 5,000daltons to about 49,000 daltons), and/or from about 90000 daltons toabout 200,000 daltons and/or about 200,000 daltons to about 500,000daltons (e.g. about 300000 daltons to about 450000 daltons). When astructurally different water-soluble polymer is also present, it mayconveniently have a higher molecular weight, for example a molecularweight greater than about 500,000 daltons.

In a related aspect, the disclosure provides pharmaceutical filmcompositions, comprising: (i) dexmedetomidine or a pharmaceuticallyacceptable salt thereof; (ii) a polymer component consisting of a firstwater-soluble polymer having a molecular weight less than about 60,000daltons (e.g. about 5,000 daltons to about 49,000 daltons), and one ormore second-water soluble polymers having a molecular weight greaterthan about 60,000 daltons; and, optionally, (iii) one or morepharmaceutically acceptable carriers.

In another related aspect, the disclosure provides pharmaceutical filmcompositions consisting essentially of: (i) dexmedetomidine or apharmaceutically acceptable salt thereof; (ii) a polymer componentconsisting of a first water-soluble polymer having a molecular weightless than about 60,000 daltons (e.g. about 5,000 daltons to about 49,000daltons), and one or more second-water soluble polymers having amolecular weight greater than about 60,000 daltons; and, optionally,(iii) one or more pharmaceutically acceptable carriers.

In yet another aspect, the disclosure provides pharmaceutical filmcompositions consisting of: (i) dexmedetomidine or a pharmaceuticallyacceptable salt thereof; (ii) a polymer component consisting of a firstwater-soluble polymer having a molecular weight less than about 60,000daltons (e.g. about 5,000 daltons to about 49,000 daltons), and one ormore second water-soluble polymers having a molecular weight greaterthan about 60,000 daltons; and, optionally, (iii) one or morepharmaceutically acceptable carriers.

Examples of one or more first water-soluble polymers are selected fromthe group consisting of hydroxypropyl cellulose (HPC), hydroxyethylcellulose, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose, methyl cellulose and mixtures thereof, including mixtures ofthe same polymer having different molecular weights.

Examples of one or more second water-soluble polymers are selected fromthe group consisting of hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, carboxy methylcellulose,methylcellulose and mixtures thereof, including mixtures of the samepolymer having different molecular weights. Polyethylene oxide (PEO) mayalso be present herein as a second water-soluble polymer or may bedescribed separately hereinafter in the pharmaceutical film compositionsas an example of a pharmaceutically acceptable carrier, or moreparticularly, as a mucoadhesive agent.

In one embodiment, the weight ratio of said first water-soluble polymerto said second water-soluble polymer(s) (including PEO when present inthe film) in the entire film composition is from about 2:1 to about1:50, for example about 1:1 to about 1:40, including about 1:1, 1:2,1:3, 1:5, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15,1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27,1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39,1:40.

In a further embodiment, the weight ratio of said first water-solublepolymer to said second water-soluble polymer(s) (including PEO whenpresent in the film) in the entire film composition is from about 1:10to about 1:30, about 1:15 to about 1:25 or about 1:15 to about 1:20. Incertain aspects, a ratio of about 1:15 to about 1:20 provides beneficialfunctional effects.

Examples of other water-soluble polymers which may be included in thefilm with the first water-soluble polymer/second water-soluble polymeror replace such polymer(s) include povidone (polyvinylpyrrolidone),copovidone (copolymers of N-vinyl-2-pyrrolidone and vinyl acetate),polyvinyl alcohol, polyethylene glycol, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl copolymers, polydextrose,pullulan, carboxymethyl cellulose, sodium alginate, chitosan, xanthangum, tragancanth gum, guar gum, acacia gum, arabic gum, starch,carrageenan, gelatin and mixtures thereof.

The water-soluble polymer component, including water-soluble polymercarriers when present, may conveniently comprise about 40% to about99.8%, about 50% to about 99.7%, about 60% to about 99.6% of the filmcomposition, based on the weight of the film on a dry weight basis.

In one aspect, the polymer component for the film composition comprisesa first water-soluble polymer present in an amount of from about 2% toabout 15% on a dry weight basis of the polymer component (e.g. at about3% to about 8% w/w of the total film weight). This water-soluble polymermay conveniently have a molecular weight from about 5,000 daltons toabout 49,000 daltons. Examples of suitable such water-soluble polymersinclude those selected from the group consisting of hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,carboxymethyl cellulose, methyl cellulose, and mixtures thereof.

In a further aspect, low molecular weight hydroxypropyl cellulose may bepresent in the film at about 3% to about 8% w/w of the total filmweight.

In a further aspect, the one or more second water-soluble polymers(including water-soluble polymer carriers such as polyethylene oxide)may, for example, be present in an amount of from about 50 to about 98weight percent on dry weight basis of the polymer component. The one ormore second water-soluble polymers each has a molecular weight greaterthan 60,000 daltons; for example, from about 90,000 daltons to about1,500,000 daltons, especially when the polymer is selected from thegroup consisting of polyethylene oxide, hydroxypropyl cellulose,hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, methylcellulose, and mixtures thereof.

In one aspect, the one or more second water-soluble polymers maytogether be present in the film at about 25% to about 40% w/w of thetotal film weight when the one or more second water-soluble polymerseach has a molecular weight from about 90,000 daltons to about 200,000daltons and/or from about 200,000 daltons to about 500,000 daltons, andthe polymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,carboxy methylcellulose, methylcellulose, and mixtures thereof.

In another aspect, a polyethylene oxide may be present in the film atabout 50% to about 60% w/w of the total film weight.

In one embodiment, the polymer component for the film compositionconsists of a low molecular weight, water-soluble polymer (e.g., havinga molecular weight less than about 60,000 daltons) and one or more highmolecular weight polymers (e.g., having a molecular weight greater about60,000, up to about 1,500,000 daltons when a polyethylene oxide isincluded in the polymer mixture or up to about 500,000 daltons when apolyethylene oxide is not included in the polymer mixture). This polymercombination, especially when the polymers are a combination ofhydroxypropyl cellulose and polyethylene oxide, lends certain advantagesto the tensile strength and pharmacokinetics of the film composition.

In one aspect, the present disclosure provides a thin film compositioncomprising, e.g. consisting essentially of:

-   -   (i) a therapeutically effective amount of dexmedetomidine or a        pharmaceutically acceptable salt thereof;    -   (ii) a polymer component consisting of one or more water-soluble        polymers: and    -   (iii) one or more pharmaceutically acceptable carriers.

In one embodiment, the present disclosure provides a thin filmcomposition comprising, e.g. consisting essentially of:

-   -   (i) a therapeutically effective amount of dexmedetomidine or a        pharmaceutically acceptable salt thereof;    -   (ii) a polymer component consisting of: (a) one or more first        water-soluble polymer (e.g. hydroxypropyl cellulose,        hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxy        methylcellulose, methylcellulose, and mixtures thereof) having a        molecular weight from about 5,000 daltons to about 49,000        daltons, for example, in about 2 to about 15 weight percent on        dry weight basis of the total polymer component; and (b) one or        more second water-soluble polymers (e.g. polyethylene oxide,        hydroxypropyl cellulose, hydroxypropyl methylcellulose,        hydroxyethyl cellulose, carboxy methylcellulose,        methylcellulose, and mixtures thereof) having a molecular weight        greater than 60,000 daltons, such as greater than 100000        daltons, for example in about 50 to about 98 weight percent on        dry weight basis of the total polymer component; and    -   (iii) one or more pharmaceutically acceptable carriers.

The molecular weight of hydroxypropyl cellulose, when present in thefilm of the present disclosure, may be varied, and may be present asboth a low molecular weight, water-soluble polymer and as one or morehigh molecular weight, water-soluble polymers. In some embodiments, themolecular weight may be less than about 60,000 daltons (e.g. about 5,000daltons to about 49,000 daltons). In other embodiments the molecularweight may be in the range from about 90,000 daltons to about 200,000daltons. In yet other embodiments, the molecular weight may be in therange from about 200,000 daltons to about 500,000 daltons.

Hydroxypropyl cellulose, when part of the film composition includingpolyethylene oxide, may conveniently be present in the range from about10% to about 90% by weight on a dry weight basis of the polymercomponent, e.g. about 20% to about 80% by weight on dry weight basis ofthe polymer component, e.g. about 20% to about 50% by weight on dryweight basis of the polymer component, e.g. about 25% to about 45% byweight on dry weight basis of the polymer component.

The molecular weight of polyethylene oxide, when present in the film ofthe present disclosure, may also be varied. In some embodiments, awater-soluble, high molecular weight polyethylene oxide may be used, forexample, to increase muco-adhesivity of the film. In certainembodiments, the molecular weight may range from about 100,000 daltonsto about 1,500,000 daltons, including about 100,000, 200,000, 300,000,600,000, 900,000 or 1,000,000 daltons. In some embodiments, it may bedesirable to use a combination of polyethylene oxide having a molecularweight of about 600,000 daltons to about 900,000 daltons withpolyethylene oxide having a molecular weight of about 100,000 daltons toabout 300,000 daltons in the polymer component.

Polyethylene oxide, when part of the film composition, may convenientlybe present range from about 30% to about 90% by weight on a dry weightbasis of the total polymer component, e.g. about 40% to about 85% byweight on a dry weight basis of the polymer component, e.g. about 55% toabout 80% by weight on a dry weight basis of the polymer component.

Such film compositions may contain the drug dispersed within the film,or micro-deposited onto a surface of the film. When micro-deposited onthe surface of a “placebo” film, the drug may conveniently be added aspart of a dexmedetomidine composition as one or more droplets in aliquid carrier, such as a solvent (e.g. an alcohol such as ethanol),optionally together with one or more (e.g. two) water-soluble polymersand/or pharmaceutically acceptable carriers. Suitable water-solublepolymers include (1) a low molecular weight, water-soluble polymer, forexample a low molecular weight, water-soluble polymer having a molecularweight of less than about 60,000 daltons (e.g. a molecular weight ofabout 5,000 daltons to about 49,000 daltons and optionally (2) one ormore (e.g. one or two) high molecular weight, water-soluble polymers,for example a high molecular weight, water-soluble polymer having amolecular weight of greater than about 60,000 daltons (e.g. a molecularweight of from about 60,000 daltons to about 150,000 daltons such ashydroxypropyl cellulose (77,000 MW), hydroxypropyl cellulose (80,000MW), hydroxypropyl cellulose (90,000 MW), or hydroxypropyl cellulose(140,000 MW)) and/or a high molecular weight, water-soluble polymerhaving a molecular weight of greater than about 60,000 daltons (e.g. amolecular weight of from about 200,000 daltons to about 900,000 daltonssuch as hydroxypropyl cellulose (340,000 MW), hydroxypropyl cellulose(370,000 MW), polyethylene oxide (200,000 MW) or polyethylene oxide(600,000 MW)). Each water-soluble polymer may independently be selectedfrom the group consisting of hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,polyethylene oxide and methyl cellulose, e.g. hydroxypropyl celluloseand/or polyethylene oxide.

In one aspect, the dexmedetomidine composition comprises dexmedetomidinehydrochloride, a low molecular weight polymer which is hydroxypropylcellulose and one or two high molecular weight polymers which are eachhydroxypropyl cellulose in an ethanol solvent.

In one aspect, the dexmedetomidine composition comprises hydroxypropylcellulose (40,000 MW) and one or both of hydroxypropyl cellulose(140,000 MW) and hydroxypropyl cellulose (370,000 MW).

In one aspect, the dexmedetomidine composition comprises only twohydroxypropyl celluloses, namely hydroxypropyl cellulose (40,000 MW) andhydroxypropyl cellulose (140,000 MW).

In other aspects, the dexmedetomidine composition may be added as one ormore droplets in an ethanol-based solution, optionally containing apH-neutralizing agent such as sodium hydroxide.

The viscosity of deposition solution/suspension may range from about 6cps to about 3700 cps as measured at 25° C. using a Brookfieldviscometer with a small sample adapter. As an example, it may range fromabout 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6 cpsto about 100 cps or about 6 cps to about 50 cps. In one aspect of thepresent disclosure, the viscosity of the dexmedetomidine composition isfrom about 6 cps to about 20 cps at 25° C. and a shear rate of about 7(1/s). The deposition composition may be in any form, including as asolution, emulsion, suspension or dispersion.

Following drying to remove the solvent, the film comprises a filmsubstrate (e.g. a placebo) with the dexmedetomidine composition aspreviously described but absent solvent deposited (e.g. micro-deposited)on the surface of the film substrate. The dried composition may coverthe whole of the film substrate surface or only part of the filmsubstrate surface. In one aspect, the composition appears as one or morediscrete drug-containing droplets on the film substrate surface.Alternatively, stenciling may be used to achieve a one or more definedand discrete regions of drug-containing composition on the surface ofthe film substrate.

In one aspect, the disclosure provides a dry film product comprising afilm substrate with one or more discrete drug-containing droplets on thefilm substrate surface, wherein each such drug-containing dropletcomprises dexmedetomidine or a pharmaceutically acceptable salt thereof,and hydroxypropyl cellulose of two molecular weights: hydroxypropylcellulose (40,000 MW) available as HPC-SSL, and hydroxypropyl cellulose(140,000 MW) marketed under the tradename of Klucel™ Type JF NF, andwherein the film substrate comprises hydroxypropyl cellulose of threemolecular weights: hydroxypropyl cellulose (40,000 MW), hydroxypropylcellulose (140,000 MW), and hydroxypropyl cellulose (370,000 MW)marketed under the tradename of Klucel™ Type GF NF. In one aspect, thefilm substrate also comprises polyethylene oxide (600,000 MW) availableunder the name of Sentry Polyox WSR 205 LEO NF.

In one aspect, the film comprises a deposition composition (alsoreferred to herein as a “dexmedetomidine composition”) comprising: (i)dexmedetomidine hydrochloride, present at about 9% to about 50% w/w ofthe deposition composition, e.g. about 15% to about 25% w/w of thedeposition composition; (ii) hydroxypropyl cellulose (40,000 MW),present at about 5% to about 85% w/w of the deposition composition;(iii) hydroxypropyl cellulose (140,000 MW) present at about 5% to 85%w/w of the deposition composition; and (iv) hydroxypropyl cellulose(370,000 MW) present at about 0% to about 65% w/w of the depositioncomposition. The film also comprises a polymer matrix, wherein thepolymer matrix comprises: (i) hydroxypropyl cellulose (40,000 MW)present at about 3% to about 40% w/w of the polymer matrix; (ii)hydroxypropyl cellulose (140,000 MW) present at about 3% to about 40%w/w of the polymer matrix; (iii) hydroxypropyl cellulose (370,000 MW)present at about 0% to about 30% w/w of the polymer matrix, and (iv)polyethylene oxide (600,000 MW) present at about 55% to about 75% w/w ofthe polymer matrix.

The disclosure also provides a monolithic film formulation forsublingual administration. The film comprises a deposition compositioncomprising: (i) dexmedetomidine hydrochloride, present at about 1% toabout 50% w/w of the total composition; (ii) hydroxypropyl cellulose(40,000 MW), present at about 2% to about 30% w/w of the totalcomposition; (iii) hydroxypropyl cellulose (140,000 MW) present at about2% to about 30% w/w of the total composition; (iv) hydroxypropylcellulose (370,000 MW) present at about 10% to about 50% w/w of thetotal composition, (v) polyethylene oxide (600,000 MW) present at about40% to about 75% w/w of the total composition and (vi) optionally otherpharmaceutically acceptable carriers.

In certain aspects, the films disclosed herein combine several types ofhydroxypropyl cellulose (HPC) to provide a film with advantageousproperties. For example, the film composition may contain two or threeof hydroxypropyl cellulose (40,000 MW), hydroxypropyl cellulose (140,000MW) and hydroxypropyl cellulose (370,000 MW) in combination. In certainembodiments, polyethylene oxide (600,000 MW) is included with thesetypes of HPC when part of a monolithic film.

In certain film compositions, a low molecular weight hydroxypropylcellulose (e.g. 40,000 MW) is present at about 3% to about 8% (e.g.about 5%) w/w of the total film weight, a high molecular weighthydroxypropyl cellulose (e.g. 140,000 MW) is present at about 3% toabout 8% (e.g. about 5%) w/w of the total film weight, a high molecularweight hydroxypropyl cellulose (e.g. 370,000 MW) is present at about 20%to about 40% w/w of the total film weight, and a polyethylene oxide(e.g. 600,000 MW) is present at about 40% to about 70%, (e.g. about 50%to about 60%) w/w of the total film weight. In one aspect, the two highmolecular weight, water-soluble polymers are together present at about25% to about 40% w/w of the total film weight.

The selection and ratio of water-soluble polymers can be made to effectcomplete dissolution of the film composition in oral mucosal fluidswithin seconds to minutes, e.g. in about 0.25 minutes to about 15minutes, thus ensuring delivery of a therapeutically effective amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof via theoral mucosa. For example, the film compositions may reside in thesublingual region of the mouth up to about 15 minutes, up to about 10minutes, or up to about 5 minutes, including for a period of from about30 seconds to about 15 minutes, about 1 minute to about 10 minutes, orabout 1 minute to about 5 minutes.

The standard basket or paddle apparatus described in any pharmacopoeiacan be used for in vitro dissolution testing. The selection ofdissolution medium will essentially depend as per the sink conditionsand highest dose of drug. The temperature of dissolution medium shouldbe maintained at 37±0.5° C. and rpm at 50 (see Bala et al., in Int JPharm Investigation, vol. 3(2), pages 67-76).

Films disclosed herein have several functional advantages to promoterapid onset of drug effect. In certain aspects, thin films compositionsof the disclosure have a disintegration time (DT) of about 15 seconds toabout 180 seconds, about 15 seconds to about 160 seconds, about 25seconds to about 150 seconds, about 15 seconds to about 140 seconds,about 15 seconds to about 120 seconds, about 40 seconds to about 120seconds, about 50 seconds to about 120 seconds, for example about 120seconds, when applied sublingually. A disintegration time in thistime-frame provides optimal onset of drug effects.

In other certain aspects, thin film compositions of the invention havemucoadhesion properties that provide practical benefits of localizingthe film to the sublingual location and reducing, or preventing,effective removal prior to dissolution. This quality is particularlyadvantageous in a clinical setting with an agitated subject. Thus, incertain aspects, thin film compositions have a mucoadhesion force (themucoadhesion strength or shear strength) of about 50 g or above, about100 g or above, about 200 g or above, about 300 g or above, about 400 gor above, about 500 g or above, about 600 g or above, about 700 g orabove, about 800 g or above, about 900 g or above, about 1000 g orabove. In certain aspects, the mucoadhesion force is in a range of about300 g to about 4000 g, about 500 g to about 3000 g, or about 1000 g toabout 2000 g.

Burst strength of the film also contributes to drug delivery. Certainthin film compositions of the invention have a burst strength at orabove 50 g, 100 g, 200 g, 300 g, 400 g, 500 g, 600 g, 700 g, 800 g, 900g, 1000 g, 1100 g, 1200 g, 1300 g, 1400 g, 1500 g, 1600 g, 1700 g, 1800g, 1900 g, 2,000 g, 2,500 g, 3,000 g, 3500 g, 4,000 g, 4,500 g, 5,000 g,5,500 g, 6,000 g, 6,500 g, 7,000 g, 7,500 g, 8,000 g, 8,500 g, 9,000 g,9,500 g, 10,000 g or 15,000 g. For example, the burst strength may be ina range of about 200 g to about 15000 g, about 300 g to about 10,000 g,or 400 g to about 5000 g.

Pharmaceutically Acceptable Carriers

The film compositions may further comprise one or more pharmaceuticallyacceptable carriers that includes, but is not limited to, liquidcarriers, flavours, sweeteners, refreshing agents, antioxidants, pHadjusting agents, permeation enhancers, mucoadhesive agents,plasticizers, bulking agents, surfactants/non-ionic solubilizers,stabilizers, anti-foam agents, colors or the like. In certainembodiments, the film compositions are substantially free of acidicbuffer or other acidic agents.

Liquid Carriers

According to one aspect, the pharmaceutically acceptable carrierincludes a liquid carrier. The liquid carrier comprises one or moresolvents useful in the preparation of the polymer matrix (drugcontaining or placebo) and deposition composition in the filmcomposition. In some embodiments, the solvent may be water. In someembodiments, the solvent may a polar organic solvent including, but notlimited to, ethanol, isopropanol, acetone, butanol, benzyl alcohol andmixtures thereof. In some embodiments, the solvent may be a non-polarorganic solvent, such as methylene chloride, toluene, ethyl acetate andmixtures thereof. Certain solvents are alcohols, especially ethanol,water and mixtures thereof.

Desirably, the solvent content in the wet polymer matrix is at leastabout 30% by weight of the total wet weight of the total filmcomposition prior to drying. The subsequent dried film composition willdesirably contain less than about 10% by weight of solvent, moredesirably less than about 8% by weight of solvent, even more desirablyless than about 6% by weight of solvent and most desirably less thanabout 2% by weight of solvent.

Flavors/Sweeteners/Refreshing Agents

It may be beneficial to add a sweetener, flavoring agent, refreshingagent, taste-masking agent or a combination thereof to the filmcompositions to improve the film composition taste.

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof. A non-limiting representative list of examples includes mintoils, cocoa, and citrus oils such as lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot or other fruitflavors.

Certain flavors or flavoring agents include natural and artificialflavors. These flavorings may be chosen from synthetic flavor oils andflavoring aromatics, and/or oils, oleo resins and extracts derived fromplants, leaves, flowers, fruits and so forth, and combinations thereof.Non-limiting flavor oils include: spearmint oil, cinnamon oil,peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil ofnutmeg, oil of sage, and oil of bitter almonds. Also useful areartificial, natural or synthetic fruit flavors such as vanilla,chocolate, coffee, cocoa and citrus oil, including lemon, orange, grape,lime and grapefruit, and fruit essences including apple, pear, peach,strawberry, raspberry, cherry, plum, pineapple, apricot or the like.These flavorings can be used individually or in combination. Commonlyused flavors include mints such as peppermint, artificial vanilla,cinnamon derivatives, and various fruit flavors, whether employedindividually or in combination. Flavorings such as aldehydes and estersincluding cinnamylacetate, cinnamaldehyde, citral, diethylacetal,dihydrocarvyl acetate, eugenyl formate, p-methylanisole, or the like mayalso be used. Further examples of aldehyde flavorings include, but arenot limited to acetaldehyde (apple); benzaldehyde (cherry, almond);cinnamaldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime);neral, i.e. beta citral (lemon, lime); decanal (orange, lemon); ethylvanillin (vanilla, cream); heliotropine, i.e., piperonal (vanilla,cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spicyfruity flavors); butyraldehyde (butter, cheese); valeraldehyde (butter,cheese); citronellal (modifies, many types); decanal (citrus fruits);aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehydeC-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexenal,i.e. trans-2 (berry fruits); tolyl aldehyde (cherry, almond);veratraldehyde (vanilla); 12,6-dimethyl-5-heptenal, i.e. melonal(melon); 2 dimethyloctanal (greenfruit); and 2-dodecenal (citrus,mandarin); cherry; grape and mixtures thereof. In one embodiment, theflavor is a peppermint oil flavour available as peppermint oil, NF.

The amount of flavoring agent employed is normally a matter ofpreference, subject to such factors as flavor type, individual flavor,and strength desired. The amount may be varied in order to obtain theresult desired in the final product. Such variations are within thecapabilities of those skilled in the art without the need for undueexperimentation. In general, amounts of about 0.1% to about 30 wt % maybe used in the films to supply flavoring.

Suitable sweeteners include both natural and artificial sweeteners.Non-limiting examples of suitable sweeteners include, e.g.:water-soluble sweetening agents such as monosaccharides, disaccharidesand polysaccharides such as xylose, ribose, glucose (dextrose), mannose,galactose, fructose (levulose), sucrose (sugar), high fructose cornsyrup, maltose, invert sugar (a mixture of fructose and glucose derivedfrom sucrose), partially hydrolyzed starch, corn syrup solids, anddihydrochalcones; water-soluble artificial sweeteners such as thesoluble saccharin salts, i.e., sodium or calcium saccharin salts,cyclamate salts, the sodium, ammonium or calcium salt of3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide, the potassiumsalt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide(acesulfame-K), the free acid form of saccharin or the like; dipeptidebased sweeteners, such as L-aspartic acid derived sweeteners, such asL-aspartyl-L-phenylalanine methyl ester (aspartame),L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamidehydrate, methyl esters of L-aspartyl-L-phenylglycerin andL-aspartyl-L-2,5, dihydrophenylglycine,L-aspartyl-2,5-dihydro-L-phenylalanine,L-aspartyl-L-(1-cyclohexyen)-alanine or the like; water-solublesweeteners derived from naturally occurring water-soluble sweeteners,such as a chlorinated derivatives of ordinary sugar (sucrose), known,for example, as sucralose; and protein based sweeteners such asthaurnatoccous danielli (Thaurnatin I and II), naturally occurring highintensity sweeteners, such as Lo Han Kuo, stevia, steviosides, monellin,and glycyrrhizin. In one embodiment, the sweetener is sucralose.

Refreshing agents, also called cooling agents, are chemicals thattrigger the cold sensitive receptors creating a cold sensation.Refreshing agents that can be added to the film compositions includementhol, thymol, camphor and eucalyptol. In one embodiment, therefreshing agent is menthol.

Flavoring agents, sweeteners and refreshing agents can be added inconventional quantities, generally up to a total amount of about 0.01%to about 10% of the weight of the film on a dry weight basis, e.g. fromabout 0.1% to about 7% of the weight of the film on a dry weight basis,e.g. about 0.1% to about 5% based on the weight of the film on a dryweight basis.

Other taste-masking agents include, for example polymers, oils, orwaxes. In one embodiment, dexmedetomidine or a pharmaceuticallyacceptable salt thereof is coated with a taste-masking agent prior toformulation of the film compositions.

In some embodiments, if a taste-masking agent is used to coat the activeingredient, it may be present in an amount of from about 5% to about 80%by weight of the particle or granule containing the active ingredient.In another embodiment, the taste-masking agent is present in an amountfrom about 25% to about 35% by weight of the particle or granulecontaining the active ingredient. The precise loading of the activeingredient in the taste-mask coated particle or granule is a function ofmany parameters, including the specific form of the active ingredientused (i.e. free base or salt thereof), the coating, and any flavorspresent in the particle or granule or in the film-forming polymermatrix.

Dexmedetomidine or a pharmaceutically acceptable salt thereof may betaste-masked with the above-described taste-masking agents by a varietyof techniques. Useful coating techniques include, but are not limitedto, fluidized bed coating, spray congealing coating, agglomeration orgranulation coating, entrapment coating, coacervation coating, infusioncoating, spin coating, ion exchange coating or the like.

Antioxidants

The film compositions may advantageously employ an antioxidant or oxygenscavenger to prevent or reduce oxidative degradation of dexmedetomidineor a pharmaceutically acceptable salt thereof prior to use. Examples ofoxygen scavengers or antioxidants that substantially improve long-termstability of the film composition against oxidative degradation includesulfite salts, such as sodium sulfite, sodium bisulfite, sodiummetabisulfite and analogous salts of potassium and calcium.

A suitable amount of the sulfite salt (e.g., sodium sulfite) is up toabout 5%, e.g. about 0.001% to about 2% based on the weight of the filmcomposition on a dry weight basis.

pH-Adjusting Agents/pH-Neutralizing Agents

The absorption of dexmedetomidine or a pharmaceutical acceptable saltthereof through the oral mucosa may increase when in an alkalinemicroenvironment. As an example, this may be achieved when the filmcompositions are maintained at a pH of above 6, from about 6 to about 9,or about 6.5 to about 8. In some embodiments, the film may include analkaline substance that increases the pH of the film product.Non-limiting examples of pH-adjusting/pH-neutralizing agents includebicarbonates (e.g., sodium bicarbonate), citrates (e.g., potassiumcitrate), carbonates (e.g., calcium carbonate), lactates (e.g., sodiumlactate), acetates (e.g., calcium acetate), alkaline buffer (e.g.glycine), sodium hydroxide, sodium chloride or the like.

An alkaline buffer, such as glycine, is one example of a pH-neutralizingagent.

The pH-adjusting agents/pH-neutralizing agents can be added into thefilm composition of in amounts effective to stabilize the pH within thedesired pH range. A suitable amount of pH-adjusting/pH-neutralizingagent present in the film composition includes, for example, up to about10%, e.g. about 1% to about 5% based on the weight of the filmcomposition on a dry weight basis.

Conversely, it has been shown (Table 24 in Example 2 hereinafter;comparative formulation 11) that the addition of an acidic buffer (forexample lactate buffer) and/or acidic agent (for example, lactic acid)to the film composition has a detrimental effect on thepermeability/diffusion of the active ingredient across the oral mucosa.

Permeation Enhancer Agents

To further promote absorption of dexmedetomidine or a pharmaceuticalacceptable salt thereof through the oral mucosa and reduce the amount ofdexmedetomidine that is introduced into the gastrointestinal tract, itmay be advantageous to add a permeation enhancer agent (i.e. apenetration enhancer) to a film composition. Certain effectivepenetration enhancers that promote absorption of dexmedetomidine or apharmaceutically acceptable salt thereof across the oral mucosa includealcohols. An alcohol penetration enhancer, such as butanol, canconveniently be added to the film composition in an amount of up toabout 10%, e.g. about 0.1% to about 5%, e.g. about 1% to about 3% basedon the weight of the film composition on a dry weight basis.

Mucoadhesive Agents

In order to promote adhesion of the film composition to the oral mucosa,it may be advantageous to add a mucoadhesive agent to a filmformulation. Examples of mucoadhesive agents that can be added to thefilm composition include, but are not limited to, sodium alginate,sodium carboxymethyl cellulose, guar gum, polyethylene oxide,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, karya gum, methylcellulose, retene, tragacanth and the like.One mucoadhesive agent is polyethylene oxide, which may conveniently beadded to the film composition in an amount of from about 20% to about90%, e.g. about 40% to about 70% based on the total weight of the filmcomposition on a dry weight basis. It will be understood thatwater-soluble mucoadhesive agents that are polymers, such aspolyethylene oxide, are also within the definition of a secondwater-soluble polymer as previously described under the term “polymercomponent”.

Plasticizers

Plasticizers can be advantageously employed in the film compositions, asneeded, to suitably modify the flexibility of the film to facilitateprocessing and allow the film to easily conform to the shape of the partof the oral cavity to which the film is applied. Plasticizers that canbe effectively employed herein include polyethylene glycol, propyleneglycol, tributyl citrate, triethyl citrate and glycerol. Depending onthe selected film-forming polymer(s) and other components of the filmformulation, a suitable amount of plasticizer included in the filmcomposition may typically be up to about 10%, e.g. about 0.1% to about5%, e.g. about 0.5% to about 5% based on the weight of the film on a dryweight basis. For certain applications, higher molecular weightpolyethylene glycols may be utilized, including polyethylene oxide.

Bulking Agents

Bulking agents (i.e. fillers) may be added as desired to increase thesize of the finished film product to facilitate processing andmanufacturing, or to modify properties (e.g., increase or decreaseresidence time or increase stiffness) of the film formulation. Suitablefillers that can be added to a film composition of include starch,calcium salts, such as calcium carbonate, and sugars, such as lactose,glucose, sucrose, mannose, sorbitol, mannitol, galactitol, sucralose,trehalose and combinations thereof. The amount of filler that canconveniently be added to the film formulation is typically up to about25%, e.g. about 0.5% to about 20%, e.g. about 1% to about 15%, e.g.about 2% to about 10%, based on the weight of the film composition on adry weight basis.

Surfactants/Non-Ionic Solubilizers

The film typically incorporates at least one surfactant/non-ionicsolubilizer including, for example, but not limited to, a poloxamer,polyoxyl hydrogenated castor oil, glyceryl polyethylene glycoloxystearates, fatty acid glyceryl polyglyceryl esters, polyglycerylesters, and combinations thereof. The amount of surfactant(s) that canbe added to the film composition is typically up to about 5%, e.g. about0.5% to about 3%, e.g. about 1% to about 3% based on the weight of thefilm composition on a dry weight basis.

Anti-Foaming Components

Anti-foaming and/or de-foaming components may also be used in a filmcomposition. These components aid in the removal of air, such asentrapped air, from the film compositions. Such entrapped air may leadto non-uniform films. Simethicone is an example of a useful anti-foamingand/or de-foaming agent, although other anti-foaming and/or de-foamingagents may suitable be used. An anti-foaming and/or de-foaming agentsuch as simethicone may be added to the film composition in an amountfrom about 0.01% to about 5.0%, more desirably from about 0.05% to about2.5%, and most desirably from about 0.1% to about 1.0% based on theweight of the film composition on a dry weight basis.

Colorants

Color additives that may be included in a film composition include food,drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), orexternal drug and cosmetic colors (Ext. D&C). These colors are dyes,their corresponding lakes, and certain natural and derived colorants.Lakes are dyes absorbed on aluminium hydroxide. Other examples of coloradditives include known azo dyes, organic or inorganic pigments, orcoloring agents of natural origin. Certain examples of color additivesare inorganic pigments, such as oxides of iron or titanium, added inconcentrations ranging from about 0.001% to about 10%, e.g. about 0.01%to about 3%, based on the weight of the film composition on a dry weighbasis. In one embodiment, the color used for the dexmedetomidinecomposition (i.e. the deposit composition) is different from the colorused for the film substrate (e.g. the placebo film).

One color of the monolithic film and the film substrate of themicro-deposited film is emerald green, and available as Fast EmeraldGreen Shade (06507). One color of the dexmedetomidine composition (i.e.the deposit composition) is a different color from the color of the filmsubstrate, e.g. blue (available as FD&C Blue No. 1).

Manufacture of Film Compositions:

The film compositions may be prepared as disclosed herein.

In general, one of the methods of preparing monolithic thin filmformulations involves casting the liquid formulation as a continuous webin the form of wide and long rolls on a continuous substrate (e.g. paperor polyester liners which may or may not have release coatings) to formwhat is sometimes referred to as a master roll. The manufacturingprocess includes drying the liquid formulation to remove solvents(aqueous and/or non-aqueous) to yield the thin film on the substrate.The master rolls thus formed are then converted into smaller unit dosesthrough roll slitting and individual unit dose die-cutting. The unitdoses are then transferred from the manufacturing substrate for primaryproduct packaging.

As an example, solvent casting may conveniently be used to prepare thepolymer film matrix. If the active ingredient is part of the polymerfilm matrix, the active ingredient, polymer(s) and other ingredients(e.g. carriers) are mixed in a solvent prior to preparing the polymerfilm matrix. Generally a low shear agitator can be used for bulk mixingand efficient heat transfer while an inline homogenizer can be used forhigh shear dispersion. The mixer is capable of applying vacuum duringprocessing to eliminate entrapment of air bubbles in the mixture, whichmanifest as film defects during the subsequent coating process. Theingredients can be added to the mixer in any order and therefore theprocess is not limited by the order of addition of each ingredient.

During the coating process the mixture is transported to the coatinghead via a controlled metering pump to assure consistent delivery of thefluid. Coating may utilize a knife-over-roll coating head, reverse rollcoating head, or a slot-die coating head based on which technique ismost appropriate for the fluid rheology and the substrate to be coated.Those skilled in the art of coating processes appreciate the varioustechniques and be able to determine the appropriate coating techniquebased upon the required film parameters. During the coating process, thefluid is deposited onto a release liner and then conveyed through a“drying tunnel.”

During the drying process, forced hot air is applied to the top side ofthe coating, to the bottom side of the coating, or to any combination oftop and bottom sides of the coating to achieve a film that contains lessthan or equal to the specified residual solvent level. Drying ovens canbe of any length but are typically between 2-10 meters in length.Multiple drying ovens can be sequentially staged so that the wet coatingpasses through multiple drying ovens, each of which can be set todifferent drying temperatures of air pressures. During the dryingprocess the coater may run at line speeds between 0.25-5 meters/minuteand the line speed is dictated by the efficiency of the drying processand the specified residual solvent level required for a particular filmproduct. After the film coating has exited the oven, it is wound up ontoa core.

In addition to solvent casting, other examples for preparing a polymerfilm matrix include a semi-solid casting method, solid dispersionextrusion method, rolling method, hot melt extrusion method and thecombination thereof.

“Casting” refers to the method in which polymers and additionalingredients (including the active agent) may be dissolved or slurried ina suitable solvent, any entrapped air is removed, the resulting mixturecast onto a suitable substrate, and dried to remove solvent to form afilm (e.g. a thin film). The film is then cut into any desired shape andsize.

In one embodiment of the solvent casting method, a solution comprisingone or more polymers (and optionally one or more suitablepharmaceutically acceptable carriers) is mixed with a solution of theactive ingredient (and any other pharmaceutically acceptable carriers),any entrapped air is removed (e.g. under vacuum), and the resultingmixture cast onto a suitable substrate and dried to remove solvent toform a film (e.g. a thin film).

In another embodiment of the solvent casting method, all the filmcomposition ingredients are mixed together in a solvent to produce asolution or slurry, any entrapped air is removed (e.g. under vacuum) andthe resulting mixture cast onto a suitable substrate and dried to removesolvent to form a film (e.g. a thin film).

In a further embodiment, when the active ingredient is dispersed withinthe film polymer matrix (as opposed to deposition on the surface of the“placebo” polymer matrix), the active ingredient may be substantiallyuniformally distributed throughout the polymer matrix.

If, alternatively, the active ingredient is present on the surface ofpolymer film matrix, a “placebo” polymer film matrix (i.e. containing nodrug) is initially prepared as a continuous polymer film matrix, and theactive ingredient as part of a suitable composition (the dexmedetomidinecomposition) is directly deposited onto the surface of the driedcontinuous polymer film matrix. In another embodiment, a “placebo”polymer matrix is formed as a continuous web that is cut into individualunits prior to depositing the dexmedetomidine composition to the surfaceof “placebo” polymer matrix. One advantage of micro-deposited matrixcompositions and the method used to prepare them is that the final unitdoses are less susceptible to variation in the amount of dexmedetomidinepresent than can occur during the preparation of conventionaldrug-containing monolithic films. Micro-deposition helps to ensure thata relatively more precise and consistent volume of formulation anddexmedetomidine is deposited. Another advantage of micro-depositedmatrix compositions and the method used to prepare them is thatdifferent doses can be produced from the same roll of film substrate.The dose either depends on the number of droplets that are applied to acertain area of the substrate or the way the film is cut afterapplication of the droplets is a consistent pattern. Conversely, indrug-containing monolithic films, the process only allows for thepreparation of units containing the same dose of drug.

In a detailed embodiment of the solvent casting method, a solutioncomprising one or more polymers (and optionally any suitablepharmaceutically acceptable carriers) is prepared, any entrapped is airremoved (e.g. under vacuum), and the resulting mixture cast onto asuitable substrate and dried to remove solvent to form a film (e.g. athin film). Separately, the active ingredient and any other necessaryingredients, e.g. pharmaceutically acceptable carrier(s) and/or polymercomponent, are dissolved/dispersed in a liquid carrier to form an activeagent-containing solution or slurry. The resultant active agent solutionor slurry is then deposited onto the previously prepared film (i.e.“placebo” polymer matrix) surface.

According to certain exemplary embodiments, the method of depositing theactive agent solution or slurry onto a “placebo” polymer matrix isaccomplished by direct dispensing as described in more detail below. Incertain alternate exemplary embodiments, direct dispensing may also beperformed with a needle or array of needles.

Broadly methods of depositing an active ingredient onto a “placebo”polymer matrix, in accordance with exemplary embodiments, employdispensing a small volume of the active ingredient, typically between 1μL to about 5000 μL, 1 μL to about 100 μL, 1 μL to about 500 μL, 250 μLto about 750 μL, alternatively between 500 μL to about 1000 μL,alternatively between 1 μL to about 1000 μL, alternatively between 500μL to about 1500 μL, alternatively between 1000 μL to about 2000 μLalternatively between 1500 μL to about 2500 μL, alternatively between2000 μL to about 3000 μL directly, alternatively between 2500 μL toabout 3500 μL, alternatively between 3000 μL to about 4000 μL,alternatively between 3500 μL to about 4500 μL, alternatively between4000 μL to about 5000 μL directly on to a surface of the “placebo”polymer matrix. In some embodiments, the entire volume is dispensed in asingle step, although for total volumes higher than 10 microliters, itmay be desirable to serially dispense multiple iterations of smallervolumes adjacent and/or overlying one another (e.g. in a linear fashion)to form the micro-deposited matrix composition.

Dexmedetomidine may be dispensed from a dispenser head by a force thatmoves the liquid from reservoir in, or connected to, the dispenser headto the surface of the “placebo” polymer matrix. This may be achieved bypositive displacement pumping through the dispensing head positionedover the surface of “placebo” polymer matrix. The “placebo” polymermatrix may be a continuous polymer film sheet or single unit polymer.The dispenser head is typically, not necessarily, a needle like tip ofthe type used in the aforementioned micro-deposition processes.

The geometry of dexmedetomidine deposition formed by direct dispensingin accordance with exemplary embodiments may be of any type. In someembodiments, the active formulation may be dispensed in a circularshape, as will occur by expressing the formulation from a cylindricaltip in which the surface energy of the substrate surface is uniform. Inaccordance with other embodiments, square, rectangle, or even morecomplex polygon shapes may be employed. This may be achieved byproviding a dispenser head in which dexmedetomidine solution or slurryexits the head and is pinned between the head and target surface toestablish the desired shape. Thus, if the geometry of the dispenser'shead surface closest to “placebo” polymer matrix is rectangular, thenrectangular deposit is generated.

Alternatively, a single unit dose may be formed by repeated smallerdispensing cycles from one or more dispensing units. Each dispenser headmay be attached to a robotic arm that controls where dexmedetomidineliquid formulation is deposited on the “placebo” polymer matrix.Alternatively, the platform on which “placebo” polymer matrix is mountedmay be motorized to move the “placebo” polymer matrix as the depositionliquid formulation is being dispensed from a fixed dispenser head. Theseconfigurations afford the ability to vary the size and shape of the doseas needed.

It will be appreciated that other ways may also be employed to dispensedexmedetomidine liquid formulation of various geometries. For example,the surface energy of the “placebo” polymer matrix may be modified toresult in better wetting by the dexmedetomidine liquid formulation. Inone embodiment, a corona or plasma treatment using a mask with openingsof the geometry to be obtained provides a well-defined region on thesurface of “placebo” polymer matrix of increased surface energy thatpromotes fluid migration to cover the treated area. In anotherembodiment, the surface energy of the formulation being dispensed may bemodified or tailored to achieve a desired flow characteristic during andafter dispensing. In yet another embodiment, a dam or frame in thedesired geometry is provided on the “placebo” polymer matrix, followedby dispensing the liquid dexmedetomidine from the dispensing head intothe defined area to generate a deposit with a specific geometry anduniformity. The dexmedetomidine composition is deposited on the surfaceof the “placebo” polymer matrix within the framed area in sufficientvolume to fill the framed area at the required depth. This stencilingtechnique allows the “placebo” polymer matrix to provide a peripheralseal around the active layer when the film is applied to mucosa. Thiscan prevent leakage of the active ingredient from the periphery of theactive layer into the oral cavity and further helps to ensure that allof the drug is delivered via the desired mucosal pathway.

It will be appreciated that the fluid characteristics of thedexmedetomidine liquid formulation (the dexmedetomidine composition)being dispensed may impact the ability to consistently obtain uniformfilm dispensing. For dispensing by a positive displacement pump, thefluid viscosity of the dexmedetomidine formulation is, for example, inthe range of 1 to 5000 cps as measured at 25° C. using a Brookfieldviscometer using a small sample adapter. However, the particularviscosity of the dexmedetomidine formulation within this range may varydepending upon a variety of factors depending on the characteristics ofthe deposition to be created, including how the liquid formulation isdesired to behave after it is dispensed onto the substrate, which itselfmay be a function of how a particular film geometry is to be obtained.For example, pinning the liquid film formulation so that it does notspread beyond the intended area may be influenced by the fluid'sviscosity, as well as its surface tension and the “placebo” polymermatrix surface energy.

Typically, the solvent casting method produces a film having a thicknessof from about 20 micrometers to about 1200 micrometers, e.g. about 50micrometers to about 1000 micrometers, e.g. about 70 micrometers toabout 200 micrometers. The dry film can be cut in appropriate sizes,typically an area of from about 1 square centimeter to about 15 squarecentimeters (e.g. about 1 cm² to about 3 cm²), to provide an appropriatedose of dexmedetomidine or a pharmaceutically acceptable salt thereof,e.g. in the size of length of from about 5 mm to about 15 mm (e.g. 8.8mm±0.5 mm) and width of from about 10 mm to about 30 mm (e.g. 22 mm±1.5mm).

In one embodiment, the film composition is prepared by a depositionmethod that results in a “placebo” film having, on the surface thereof,a substantially non-uniform distribution of dexmedetomidine or apharmaceutically acceptable salt thereof. In certain aspects, where thedeposition process requires or benefits from drying followingdeposition, drying ovens and/or forced hot air may be used. Dryingtemperature may vary from about 40° C. to about 80° C. Dryingtemperature is adjusted in such a manner that moisture content of filmis about ≤5%. Drying time may vary from about 5 minutes to about 180minutes, e.g. about 5 minutes to about 60 minutes. In some embodiments,drying time may be about at least 30 minutes. Optionally, gentle airflow and low temperatures (˜40-50° C.) in the drying ovens may be used.The fluid rheology of a particular deposition formulation will dictatethe particular drying parameters required. In some embodiments, dryingconditions may include heating at 70° C. for 5-10 minutes. Each unitcontains at least one spot of micro-deposition composition. Theviscosity of the micro-deposition solution/suspension (thedexmedetomidine composition) may range from about 6 cps to about 3700cps, when measured at 25° C. using a Brookfield viscometer with a smallsample adapter. For example, the viscosity is from about 6 cps to about500 cps, about 6 cps to about 200 cps, about 6 cps to about 100 cps,about 6 cps to about 50 cps, or about 6 cps to about 20 cps at 25° C.and a shear rate of about 7 (1/s).

If deposition does not require a drying step, then the process cancontinue after initial substrate drying and during slitting of masterrolls. Since the film is wide web, it is possible that multiple lanes ofdeposition can occur at the same time. It is also contemplated that thedeposition process can be accomplished using a single lane.

Additionally, if the deposition does not require drying followingdeposition, the packaging machine can be equipped with a slittingstation to control the width of the film being processed. This is astandalone station that can function in-line during the processing offinished units. Formulation can be deposited onto the surface of aplacebo slit roll by applying a single deposition apparatus in-line atthe slitting station. An air-knife and IR heater placed in-line togently blow air over the film after deposition would provide slightdrying of the deposition, despite the application not requiring drying.This reduces the amount of solvent remaining in the deposition ifnecessary. Following deposition, the film is die-cut and packaged as aunit dose.

In other embodiments, any suitable drying process may be applied such asthermal drying process. Other methods include gas forced air drying inwhich hot air is blown down on the deposit at high velocity to minimizethe boundary layer and facilitate mass transfer, drying in a box ovenand IR drying, all by the way of example.

The packed films must be stored at a controlled temperature, e.g. fromabout 15-30° C.

Another benefit of direct dispensing individual unit doses is an abilityto vacuum dry the dispensed dexmedetomidine composition onto the polymermatrix film. The use of vacuum drying provides faster drying times atlower temperatures that, in turn, affords improved productivity, lowenergy consumption (less heat) and improved film and drug stability as aresult of the lower temperatures. Vacuum drying may also yield a bettercontent uniformity and patient dosing by reduced potential for entrappedair or bubble defects. Improved productivity may be achieved by dryingmore quickly at lower pressures as well as affording integration ofother product conversion steps as part of an overall, in-line processsequence.

One example of a deposition method comprises the following steps:

-   -   (i) preparing a first composition comprising a polymer component        and one or more pharmaceutically acceptable carriers, including        a liquid carrier, and optionally other pharmaceutically        acceptable carriers;    -   (ii) solvent casting the product of step (i) to produce a        polymer matrix (“placebo” polymer matrix);    -   (iii) conveying said polymer matrix through a drying apparatus        to form a dried polymer matrix;    -   (iv) preparing a second composition comprising dexmedetomidine        or a pharmaceutically acceptable salt thereof, one or more        pharmaceutically acceptable carriers, including a liquid        carrier, and optionally other pharmaceutically acceptable        carrier(s) and a polymer component;    -   (v) depositing the dexmedetomidine composition onto the dried        polymer matrix of step (iii) as one or more droplets; and    -   (vi) drying, including allowing to dry without using a drying        method, to remove at least a portion of the liquid carrier from        the product of step (v) to produce the final product.

Additional ingredients can also be applied to the dried film by, forexample, printing, spraying, dusting, or vapor adsorption processes,among others.

The film product can be processed into unit doses by any suitabletechnique, including, for example, die-cutting or cutting across thewidth of a singular narrow roll to prepare unit doses of any desiredgeometric size or shape. The unit doses may then conveniently bepackaged with various suitable materials known in the art to preventdegradation and protect the active ingredient from adulteration.

Desirably, a series of such unit doses are packaged together inaccordance with the prescribed regimen or treatment, e.g., a 10-90 daysupply, depending on the particular therapy. Individual films may alsocomprise a backing material, which can be peeled off prior to use.

The present disclosure also provides film compositions ofdexmedetomidine or a pharmaceutically acceptable thereof, wherein thefilm has the thickness about 0.02 millimeters (20 micrometers) to about0.2 millimeters (200 micrometers), resulting in weight in the range ofabout 0.5 milligrams to about 200 milligrams. Thus, in some aspects, thefilm compositions comprise a polymer matrix monolayer having a limitedthickness allowing them to rapidly disintegrate in the oral environmentand release dexmedetomidine or a pharmaceutically acceptable saltthereof without undue discomfort to the oral mucosa. Such a compositionmay be a “placebo” layer with drug deposited on a surface or may containthe active ingredient in the polymer matrix itself.

In a further embodiment, we provide the co-administration of a film ofthis disclosure together with a long-acting dexmedetomidine formulation.Examples of long-acting dexmedetomidine formulations include transdermalpatches and depot products such as depot injections (e.g. IV or IM) orimplantable devices. Examples of transdermal patches include patchesdisclosed in published US patent/patent applications nos. US2015/0098980, US 2015/0098997, US 2015/0098983, US 2015/0098982, US2015/0098981, US 2018/0117012, US 20140328898, US 20130072532, U.S. Pat.Nos. 5,817,332, 5,217,718, 5,820,875, and 9,974,754 and relatedpatents/patent applications.

A specific embodiment provides a method of treating agitation in asubject comprising administering to a subject a film of the presentdisclosure and concurrently or subsequently administering a long-actingtransdermal patch formulation of dexmedetomidine, optionally followed bythe further administration of a film of the present disclosure.

A further specific embodiment provides a method of treating agitation ina subject comprising administering to a subject a film of the presentdisclosure and concurrently or subsequently administering a long-actingdepot injectable formulation of dexmedetomidine, optionally followed byadministration of a film of the present disclosure.

Therapeutic Use of Film Compositions:

The film compositions disclosed herein may be used for the treatment ofvarious disorders/conditions including:

-   -   Agitation associated with neurodegenerative conditions selected        from the group consisting of: Alzheimer disease, frontotemporal        dementia (FTD), dementia, dementia with Lewy bodies (DLB),        post-traumatic stress disorder, Parkinson's disease, vascular        dementia, vascular cognitive impairment, Huntington's disease,        multiple sclerosis, Creutzfeldt-Jakob disease, multiple system        atrophy, and progressive supranuclear palsy; senile dementia of        the Alzheimer type (SDAT)    -   Agitation associated with neuropsychiatric conditions selected        from the group consisting of: schizophrenia, bipolar disorder,        bipolar mania, delirium, and depression, including dementia or        mood disorders in subjects with major depression (e.g.        stress-related major depression);    -   Agitation associated with other conditions such as OPD/IPD        procedures (e.g. MRI, CT or CAT scan, lumbar puncture, bone        marrow aspiration/biopsy, tooth extraction and other dental        procedures);    -   Agitation associated with alcohol, opioid use disorder, opioid        withdrawal and substance abuse withdrawal;    -   Delirium;    -   Traumatic brain injury (TBI), including TBI subjects with        alcohol or substance use disorder (ASUD);    -   Post-Traumatic Stress Disorder (PTSD), including PTSD subjects        with alcohol or substance use disorder (ASUD);    -   Tardive dyskinesia;

The film compositions disclosed herein find particular use in thetreatment of acute agitation associated with the disorders/conditionsdescribed above.

The film compositions disclosed herein also find particular use in thetreatment of hyper-arousal associated with acute agitation in patientswith schizophrenia, bipolar disorder, and dementia.

The film compositions disclosed herein also find particular use in thetreatment of acute agitation without causing significant sedation.

The film compositions disclosed herein also find particular use in thetreatment of chronic agitation without causing significant sedation.

The film compositions disclosed herein may also be used as adjuncttherapeutics to exposure therapy for the treatment of post-traumaticstress disorder (PTSD).

The film compositions disclosed herein may also be used for thetreatment of PTSD with or without standard treatment of PTSD.

The film compositions disclosed herein also find particular use in thetreatment of post-traumatic stress disorder (PTSD) associated withalcohol or substance use disorder (ASUD).

The film compositions disclosed herein may also be used as an adjuncttherapeutic before, during or after Exposure Therapy (ET) for patientsundergoing ASUD treatment co-morbid with PTSD or traumatic brain injury.

In one aspect, the film compositions disclosed herein may be used forthe treatment of patients with PTSD that suffer from alcohol and/orsubstance abuse, for example in treating PTSD patients who are seekingto overcome alcohol and/or substance dependence and are susceptible toalcohol and/or substance abuse withdrawal symptoms.

In another aspect, the film compositions disclosed herein may be usedfor the treatment of patients with TBI that suffer from alcohol and/orsubstance abuse, for example in treating TBI patients who are seeking toovercome alcohol and/or substance dependence and are susceptible toalcohol and/or substance abuse withdrawal symptoms.

The patients, also referred to as subjects, are typically humansubjects. In aspects, the human is at least 55, at least 60, at least 65or at least 75. The methods and formulations disclosed herein thus haveuse, for example, in humans aged 55 to 75.

In one aspect, the present disclosure provides methods for treating orameliorating agitation associated with neurodegenerative conditions byadministering to such patients in need of treatment a dexmedetomidinefilm formulation as described herein.

In another aspect, the present disclosure provides methods for treatingor ameliorating agitation associated with neuropsychiatric conditions byadministering to such patients in need of treatment a dexmedetomidinefilm formulation as described herein.

In a further aspect, the present disclosure provides methods fortreating or ameliorating agitation associated with other conditions suchas OPD/IPD procedures (e.g. MRI, CT or CAT scan, lumbar puncture, bonemarrow aspiration/biopsy, tooth extraction or other dental procedures)by administering to such patients in need of treatment a dexmedetomidinefilm composition as described herein.

In a yet further aspect, the present disclosure provides methods fortreating or ameliorating agitation associated with alcohol and substanceabuse withdrawal by administering to such patients in need of treatmenta dexmedetomidine film formulation as described herein.

The dosage forms disclosed herein dissolve or disintegrate rapidly inthe patient's mouth without chewing or the need for water. Because oftheir ease of administration, such compositions are particularly usefulfor the specific needs of patients with compromised motor skills.

Typical per unit dose of dexmedetomidine or a pharmaceuticallyacceptable salt thereof include from about 0.5 micrograms to about 200micrograms, about 0.5 micrograms to about 150 micrograms, from about 1microgram to about 100 micrograms, from about 3 micrograms to about 90micrograms, from about 3 micrograms to about 80 micrograms, from about 3micrograms to 70 micrograms, from about 3 micrograms to about 60micrograms, from about 3 micrograms to 50 micrograms, from about 3micrograms to about 40 micrograms, from about 3 micrograms to about 35micrograms, from about 5 micrograms to about 35 micrograms, about 10micrograms to about 50 micrograms, about 10 micrograms to about 40micrograms, about 10 micrograms to about 35 micrograms, about 15micrograms to about 35 micrograms or about 15 micrograms to 35micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof. In certain embodiments, the per unit dose is about 10micrograms, about 15 micrograms, about 20 micrograms, about 25micrograms, about 30 micrograms, about 35 micrograms, about 40micrograms, about 45 micrograms, about 50 micrograms, about 55micrograms, about 60 micrograms, about 65 micrograms, about 70micrograms, about 75 micrograms, about 80 micrograms, about 85micrograms, about 90 micrograms, about 95 micrograms, about 100micrograms, about 110 micrograms, about 120 micrograms, about 130micrograms, about 140 micrograms or about 150 micrograms. Each unit maybe administered to the subject multiple times per day, including twice,three times, four times, five times or six times per day.

The exemplary dosage of dexmedetomidine or a pharmaceutically acceptablesalt thereof to be administered to a particular patient, will depend onthe type and extent of the condition, the overall health status of theparticular patient, the particular form of dexmedetomidine or apharmaceutically acceptable salt thereof being administered, and theparticular film formulation used to treat the patient.

Combination Therapy

In one embodiment, the present disclosure provides a film as disclosedherein, wherein the film comprises dexmedetomidine or a pharmaceuticallyacceptable salt thereof together with one or more additional therapeuticagents. Such combination therapy may be particularly useful in thetreatment of agitation in conditions caused or exacerbated by alcohol orother substance abuse, including post-traumatic stress disorder andtraumatic brain injury (TBI).

Examples of suitable additional therapeutic agents include opioidantagonists (e.g. naltrexone or naloxone), opioid partial agonists (e.g.buprenorphine, butorphanol, pentazocine or tramadol), andanti-depressants such as serotonin-norepinephrine reuptake inhibitors(e.g. amitriptyline, atomoxetine, desipramine, duloxetine, maprotiline,mefazodone, milnacipran, nefazodone, protripyline, trimipramine,reboxetine, venlafaxine, or viloxazine), or selective serotonin reuptakeinhibitors (e.g. citalopram, fluoxetine, paroxetine, sertraline,fluvoxamine, citalopram, or escitalopram). For example, a film asdisclosed herein comprising dexmedetomidine or a pharmaceuticallyacceptable salt thereof can improve the response to currently usedtreatment in subjects with PTSD, such as serotonin-norepinephrinereuptake inhibitors and selective serotonin reuptake inhibitors, forexample by achieving a more rapid response or an augmented responseprior to the initial use and after the discontinuation of theserotonin-norepinephrine reuptake inhibitor or selective serotoninreuptake inhibitor. Dexmedetomidine or a pharmaceutically acceptablesalt thereof may also be used in combination with a NMDA receptorantagonist such as ketamine to treat major depression, for exampleagitation in subjects with dementia or mood disorders associated withstress-related major depression.

In one embodiment, the present disclosure provides a film as disclosedherein, wherein the film comprises dexmedetomidine or a pharmaceuticallyacceptable salt thereof together with an opioid antagonist or apharmaceutically acceptable salt thereof.

In a further embodiment, the present disclosure provides a film asdisclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with an effectiveamount of an opioid antagonist or a pharmaceutically acceptable saltthereof for the treatment of agitation, without causing excessivesedation.

In a further embodiment, the present disclosure provides a film asdisclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with an effectiveamount of an opioid antagonist or a pharmaceutically acceptable saltthereof for the treatment of agitation associated with opioid orsubstance withdrawal.

In a specific embodiment, the present disclosure provides a film asdisclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with naltrexone or apharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides a film asdisclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with an opioid partialagonist or a pharmaceutically acceptable salt thereof.

In a further embodiment, the present disclosure provides a film asdisclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with an effectiveamount of a partial agonist or a pharmaceutically acceptable saltthereof for the treatment of agitation without causing excessivesedation.

In further embodiment, the present disclosure provides a film asdisclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with an effectiveamount of a partial agonist or a pharmaceutically acceptable saltthereof for the treatment of agitation associated with opioidwithdrawal.

In specific embodiment, the present disclosure provides a film asdisclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with buprenorphine ora pharmaceutically acceptable salt thereof.

An effective amount of dexmedetomidine or a pharmaceutically acceptablesalt thereof and opioid antagonist or partial agonist may be included inthe film of the present disclosure, so as to provide the desired effect.

In one embodiment, the film comprises about 5 micrograms to 150micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 2 mg to about 16 mg of the partial agonist per unit.More desirably, the film comprises about 5 micrograms to 150 microgramsof dexmedetomidine or a pharmaceutically acceptable salt thereof andabout 4 mg to about 12 mg of partial agonist per unit.

In another embodiment, the film comprises about 5 micrograms to 150micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 0.5 mg to about 5 mg of the opioid antagonist perunit. More desirably, the film comprises about 5 micrograms to 150micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 1 mg to about 3 mg of opioid antagonist per unit.

In one specific embodiment, the film comprises about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 0.5 mg naltreone, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 1 mg naltrexone, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 2 mg naltrexone, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 3 mg naltrexone, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 4 mg naltrexone, or any similar amounts.

In another specific embodiment, the film comprises about 10 microgramsto 60 micrograms of dexmedetomidine or a pharmaceutically acceptablesalt thereof and about 2 mg buprenorphine, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 4 mg buprenorphine, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 6 mg buprenorphine, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 8 mg buprenorphine, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 10 mg buprenorphine, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 12 mg buprenorphine, or about 10 micrograms to 60micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof and about 16 mg buprenorphine or any similar amounts.

The drug combinations hereinabove may be included in a monolithic filmof the present disclosure or a micro-deposition film of the presentdisclosure. If in a monolithic film, the present disclosure provides forthe presence of all drugs in a single matrix film layer. The drugs mayalso be present in separate monolithic films which are then combined toprovide a multi-layer film.

In one embodiment, and more conveniently, the drugs are included in amicro-deposition film of this disclosure. Thus, for example, individualdrug compositions may be added as discrete droplets to the surface ofthe film substrate (i.e. placebo film) according to the general processused and described herein to add the dexmedetomidine composition to afilm substrate. The droplets may be added in any pattern to suit thedesired unit dose requirements. The droplets may each include a colorantwhich may be the same or different for each drug composition. It may beconvenient to use different colors to distinguish the different drugs onthe surface of the film substrate.

In one embodiment, we provide a method of treating agitation in asubject comprising administering to the subject a film of the presentdisclosure with concomitant exposure therapy.

In another embodiment, examples of suitable therapeutic agents to becombined with dexmedetomidine in the film composition include selectiveserotonin reuptake inhibitors (SSRIs) such as paroxetine, sertraline,serotonin and norepinephrine reuptake inhibitors (SNRIs) such asdesipramine. In one embodiment, the present disclosure provides a filmas disclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with a selectiveserotonin reuptake inhibitor or a pharmaceutically acceptable saltthereof. In another embodiment, the present disclosure provides a filmas disclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with a serotonin andnorepinephrine reuptake inhibitor or a pharmaceutically acceptable saltthereof.

In specific embodiment, the present disclosure provides a film asdisclosed herein, wherein the film comprises dexmedetomidine or apharmaceutically acceptable salt thereof together with desipramine or apharmaceutically acceptable salt thereof.

An effective amount of dexmedetomidine or a pharmaceutically acceptablesalt thereof and ketamine or a pharmaceutically acceptable salt thereofmay be included in the film of the present disclosure, so as to providethe desired effect.

Specific Embodiments

Embodiment 1. A pharmaceutical film composition suitable for sublingualadministration, comprising:

-   -   (i) a therapeutically effective amount of dexmedetomidine or a        pharmaceutically acceptable salt thereof;    -   (ii) a polymer component consisting of one or more water-soluble        polymers; and    -   (iii) one or more pharmaceutically acceptable carriers.

Embodiment 2: A pharmaceutical film composition suitable for sublingualadministration, consisting essentially of:

-   -   (i) a therapeutically effective amount of dexmedetomidine or a        pharmaceutically acceptable salt thereof;    -   (ii) a polymer component consisting of one or more water-soluble        polymers; and    -   (iii) one or more pharmaceutically acceptable carriers.

Embodiment 3. The pharmaceutical film composition according toEmbodiment 1 or Embodiment 2, wherein said the polymer componentconsisting of at least two different water-soluble polymers.

Embodiment 4. The pharmaceutical film composition according toEmbodiment 3, wherein the first water-soluble polymer has a molecularweight from about 5,000 daltons to about 49,000 daltons and one or moresecond water-soluble polymers each have a molecular weight greater thanabout 60,000 daltons.

Embodiment 5. The pharmaceutical film composition according toEmbodiment 3 or Embodiment 4, wherein the ratio of first water-solublepolymer to second water-soluble polymer(s) (including PEO when presentin the film) in the entire film composition is from about 1:10 to about1:30, about 1:15 to about 1:25 or about 1:15 to about 1:20.

Embodiment 6. The pharmaceutical film composition according toEmbodiment 4, wherein the first water-soluble polymer is selected fromthe group consisting of hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methylcellulose, and mixtures thereof.

Embodiment 7. The pharmaceutical film composition according toEmbodiment 6, wherein the first water-soluble polymer consisting ofhydroxypropyl cellulose and/or hydroxyethyl cellulose.

Embodiment 8. The pharmaceutical film composition according toEmbodiment 4, wherein the one or more second water-soluble polymersis/are selected from the group consisting of polyethylene oxide,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxy methylcellulose, methylcellulose and mixturesthereof.

Embodiment 9. The pharmaceutical film composition according toEmbodiment 7, wherein the second water-soluble polymer(s) is/areselected from hydroxypropyl cellulose, hydroxyethyl cellulose,polyethylene oxide and mixtures thereof.

Embodiment 10. The pharmaceutical film composition according to any ofEmbodiments 1 to 9, wherein the dexmedetomidine or a pharmaceuticallyacceptable salt thereof is dexmedetomidine hydrochloride.

Embodiment 11. The pharmaceutical film composition according to any ofEmbodiments 1 to 10 in the form of a dosage unit, wherein the amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof presentper unit is from about 0.5 micrograms to about 150 micrograms, fromabout 1 microgram to about 100 micrograms, from about 3 micrograms toabout 90 micrograms, from about 3 micrograms to about 80 micrograms,from about 3 micrograms to 70 micrograms, from about 3 micrograms toabout 60 micrograms, from about 3 micrograms to 50 micrograms, about 3micrograms to about 35 micrograms, from about 3 micrograms to about 50micrograms, from about 5 micrograms to about 50 micrograms, from about 5micrograms to about 45 micrograms, from about 3 micrograms to about 40micrograms, from about 5 micrograms to about 35 micrograms, about 10micrograms to about 50 micrograms, about 10 micrograms to about 40micrograms, about 10 micrograms to about 35 micrograms, about 15micrograms to about 35 micrograms or from about 15 micrograms to about35 micrograms of dexmedetomidine or a pharmaceutically acceptable saltthereof.

Embodiment 12. The pharmaceutical film composition according to any ofEmbodiments 1 to 11, wherein dexmedetomidine hydrochloride is present inan amount of from about 0.01% to about 50% based on the weight of thefilm on a dry weight basis, e.g. from about 0.05% to about 30% based onthe weight of the film on a dry weight basis, e.g. from about 0.05% toabout 20% based on the weight of the film on a dry weight basis.

Embodiment 13. The pharmaceutical film composition according to any ofEmbodiments 1 to 12, wherein the pharmaceutically acceptable carrierincludes, but not limited to, one or more of liquid carriers, flavors,sweeteners, refreshing agents, pH adjusting agents, permeationenhancers, mucoadhesive agents, plasticizers, bulking agents,surfactants, anti-foaming agents, colorants or the like.

Embodiment 14. The pharmaceutical film composition according to any ofEmbodiments 1 to 13, wherein the film has a thickness of about 20micrometers to about 1200 micrometers.

Embodiment 15. The pharmaceutical film composition according to any ofEmbodiments 1 to 14, wherein the film, when placed sublingually, willdissolve in about 10 seconds to about 180 seconds, e.g. about 60 secondsto about 180 seconds.

Embodiment 16. The pharmaceutical film composition according to any ofEmbodiments 1 to 15, wherein the film is mucoadhesive in nature.

Embodiment 17. The pharmaceutical film composition according to any ofEmbodiments 1 to 16, wherein the disintegration time of the filmcomposition upon contacting simulated fluids is between about 10 secondsto about 180 seconds, about 15 seconds to about 180 seconds, about 30seconds to about 180 seconds, about 45 seconds to about 180 seconds,about 60 seconds to about 180 seconds, or about 60 seconds to about 140seconds; or the disintegration time of the film composition uponcontacting simulated fluids is between about 15 seconds to about 180seconds, about 15 seconds to about 160 seconds, about 25 seconds toabout 150 seconds, about 15 seconds to about 140 seconds, about 15seconds to about 120 seconds, about 40 seconds to about 120 seconds,about 50 seconds to about 120 seconds, for example about 120 seconds.

Embodiment 18: A process for preparing a pharmaceutical film compositioncomprises the steps of:

-   -   (i) preparing a mixture comprising dexmedetomidine or a        pharmaceutically acceptable salt thereof, a polymer        component(s), and one or more pharmaceutically acceptable        carriers including a liquid carrier and optionally one or more        other pharmaceutically acceptable carriers;    -   (ii) dispersing or casting the mixture on a substrate to form a        drug-containing polymer matrix; and    -   (iii) drying the drug-containing polymer matrix to remove at        least a portion of the liquid carrier to form a monolithic        drug-containing matrix film composition.

Embodiment 19: A process for preparing a pharmaceutical film compositioncomprises the steps of:

-   -   (i) preparing a monolithic matrix film composition according to        Embodiment 18, except that the composition does not contain any        dexmedetomidine or a pharmaceutically acceptable salt thereof        (i.e. a “placebo” film composition):    -   (ii) preparing a second composition comprising dexmedetomidine        or a pharmaceutically acceptable salt thereof together with one        or more pharmaceutically acceptable carriers including a liquid        carrier, and optionally one or more other pharmaceutically        acceptable carriers and/or a polymer component;    -   (iii) depositing the product of step (ii) onto the surface        “placebo” film composition of step (i), e.g. as one or more        droplets; and    -   (iv) drying the product of step (iii) to remove at least a        portion of the liquid carrier to form a matrix film composition        containing drug on the film surface.

Embodiment 20. The process according to Embodiment 19, wherein thesecond composition comprises a polymer component.

Embodiment 21. A method of treating agitation in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a pharmaceutical film compositionaccording to any of Embodiments 1 to 15.

Embodiment 22. The method according to Embodiment 21, wherein thepharmaceutical film composition is placed in the mouth of the subjectunder the tongue.

Embodiment 23. The method according to Embodiment 21 or 22, wherein theagitation is associated neurodegenerative diseases selected from thegroup consisting of Alzheimer's disease, frontotemporal dementia (FTD),dementia, dementia with Lewy bodies (DLB), post-traumatic stressdisorder (PTSD), Parkinson's disease, vascular dementia, vascularcognitive impairment, Huntington's disease, multiple sclerosis,Creutzfeldt-Jakob disease, multiple system atrophy, and progressivesupranuclear palsy.

Embodiment 24. The method according to Embodiment 21 or 22, wherein theagitation is associated neuropsychiatric conditions selected from thegroup consisting of schizophrenia, bipolar disorder, bipolar mania,delirium, and depression.

Embodiment 25. The method according to Embodiment 21 or 22, wherein theagitation is associated with conditions such as OPD/IPD procedures (e.g.MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration/biopsy,tooth extraction or other dental procedures).

Embodiment 26. The method according to Embodiment 21 or 22, wherein theagitation is associated with alcohol withdrawal, opioid use disorder,opioid withdrawal and substance abuse withdrawal.

Embodiment 27. The pharmaceutical film composition prepared according toEmbodiment 18 or Embodiment 19, wherein said polymer componentconsisting of at least two different water-soluble polymers.

Embodiment 28. The pharmaceutical film composition according toEmbodiment 27, wherein the first water-soluble polymer has a molecularweight from about 5,000 daltons to about 49,000 daltons and one or moresecond water-soluble polymers each have a molecular weight greater thanabout 60,000 daltons.

Embodiment 29. The pharmaceutical film composition according toEmbodiment 18 or Embodiment 28, wherein the ratio of first water-solublepolymer to second water-soluble polymer(s) (including PEO when presentin the film) in the entire film composition is from about 1:10 to 1:30,about 1:15 to about 1:25 or about 1:15 to about 1:20.

Embodiment 30. The pharmaceutical film composition according toEmbodiment 19 or Embodiment 28, wherein the ratio of first water-solublepolymer to second water-soluble polymer(s) (including PEO when presentin the film) in the polymer matrix composition (“placebo”) is from about1:10 to 1:30, about 1:15 to about 1:25 or about 1:15 to about 1:20.

Embodiment 31. A method of treating agitation associated with opioidwithdrawal in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of apharmaceutical film composition comprising an effective amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof and aneffective amount of opioid antagonist.

Embodiment 32. A method of treating agitation associated with opioidwithdrawal in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of apharmaceutical film composition comprising an effective amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof and aneffective amount of partial agonist.

Embodiment 33. A method of treating agitation associated withpost-traumatic stress disorder in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a pharmaceutical film composition comprising an effectiveamount of dexmedetomidine or a pharmaceutically acceptable salt thereofas adjunct therapeutic to exposure therapy.

Embodiment 34. A method of treating post-traumatic stress disorder in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a pharmaceutical filmcomposition comprising an effective amount of dexmedetomidine or apharmaceutically acceptable salt thereof as adjunct therapeutic toexposure therapy.

Embodiment 35. A method of treating post-traumatic stress disorderassociated with opioid withdrawal in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical film composition comprising aneffective amount of dexmedetomidine or a pharmaceutically acceptablesalt thereof.

Embodiment 36. A method of treating traumatic brain injury in a subjectin need thereof, the method comprising administering to the subject apharmaceutical film composition comprising an effective amount ofdexmedetomidine or a pharmaceutically acceptable salt thereof.

EXAMPLES Example 1

Thin Film Formulations

Formulation 1

TABLE 1 Dexmedetomidine hydrochloride dispersed within a polymer matrixfilm composition: Concentration Ingredients g/100 g FunctionDexmedetomidine 3.60 Active hydrochloride Hydroxypropyl cellulose 4.82Film former (MW = 40,000)  Hydroxypropyl cellulose 4.82 Film former (MW= 140,000) Hydroxypropyl cellulose 28.94 Film former (MW = 370,000)Polyethylene oxide 57.84 Film former & (MW = 600,000) mucoadhesivePurified water* q.s. Solvent (or liquid carrier) *substantially removedvia drying from the final formulation

Process: All the ingredients listed in table 1 were dissolved in waterwith stirring, cast through a fixed gap onto a release liner substrateto form a film, and subsequently dried in a lab oven at 70° C. for 30minutes to provide a thin film product.

Formulation 2:

TABLE 2 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition: Concentration Film Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Ethanol* q.s. Solvent Polymer matrix compositionHydroxypropyl cellulose 4.98 Film former (MW = 40,000)  Hydroxypropylcellulose 4.98 Film former (MW = 140,000) Hydroxypropyl cellulose 29.86Film former (MW = 370,000) Polyethylene oxide 59.70 Film former & (MW =600,000) mucoadhesive Purified water* q.s. Solvent (or liquid carrier)*substantially removed via drying from the final formulation

Process: All the polymers of the polymer matrix composition weredissolved in water with stirring, cast through a fixed gap onto arelease liner substrate to form a film and subsequently dried in a laboven at 70° C. for 30 minutes. Separately, dexmedetomidine hydrochloridewas dissolved in ethanol on a vortex mixer and then deposited (asdroplets) via volumetric pipette onto the film. Deposited drugcomposition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 3:

TABLE 3 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition: Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.34 Active SodiumChloride 0.10 pH neutralizing agent Sodium Hydroxide 0.65 pHneutralizing agent Ethanol* q.s. Solvent (or liquid carrier) Polymermatrix composition Hydroxypropyl cellulose 4.74 Film former (MW =40,000)  Hydroxypropyl cellulose 4.74 Film former (MW = 140,000)Hydroxypropyl cellulose 28.44 Film former (MW = 370,000) Polyethyleneoxide 56.86 Film former & (MW = 600,000) mucoadhesive Glycine 3.80Alkaline Buffer Sodium Hydroxide 0.33 Alkaline Buffer Purified water*q.s Solvent (or liquid carrier) *substantially removed via drying fromthe final formulation

Process: All the polymers and alkaline buffers of the polymer matrixcomposition were dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride was dissolved in ethanol on a vortex mixer, neutralizedwith excess sodium hydroxide and sodium chloride and then deposited (asdroplets) via volumetric pipette onto the film. Deposited drugcomposition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 4:

TABLE 4 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition: Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine hydrochloride 0.48Active Hydroxypropyl cellulose 2.08 Film former (MW = 40,000)  Ethanolq.s. Solvent (or liquid carrier) Polymer matrix compositionHydroxypropyl cellulose 4.87 Film former (MW = 40,000)  Hydroxypropylcellulose 4.87 Film former (MW = 140,000) Hydroxypropyl cellulose 29.23Film former (MW = 370,000) Polyethylene oxide 58.47 Film former & (MW =600,000) mucoadhesive Purified water q.s. Solvent (or liquid carrier)

Process: All the polymers of the polymer matrix composition weredissolved in water with stirring, cast through a fixed gap onto arelease liner substrate to form a film and subsequently dried in a laboven at 70° C. for 30 minutes. Separately, dexmedetomidine hydrochlorideand hydroxypropyl cellulose (MW=40,000) were dissolved in ethanol on avortex mixer and then deposited (as droplets) via volumetric pipetteonto the film. Deposited drug composition was dried in a lab oven at 70°C. for five minutes to provide the thin film product.

Formulation 5:

TABLE 5 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition: Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine hydrochloride 0.47Active Hydroxypropyl cellulose 0.28 Film former (MW = 40,000) Hydroxypropyl cellulose 0.28 Film former (MW = 140,000) Hydroxypropylcellulose 1.54 Film former (MW = 370,000) Ethanol q.s. Solvent (orliquid carrier) Polymer matrix composition Hydroxypropyl cellulose 4.87Film former (MW = 40,000)  Hydroxypropyl cellulose 4.87 Film former (MW= 140,000) Hydroxypropyl cellulose 29.23 Film former (MW = 370,000)Polyethylene oxide 58.46 Film former & (MW = 600,000) mucoadhesivePurified water q.s. Solvent (or liquid carrier)

Process: All the polymers of the polymer matrix composition weredissolved in water with stirring, cast through a fixed gap onto arelease liner substrate to form a film and subsequently dried in a laboven at 70° C. for 30 minutes. Separately, dexmedetomidine hydrochlorideand the hydroxypropyl celluloses of the drug containing composition weredissolved in ethanol on a vortex mixer and then deposited (as droplets)via volumetric pipette onto the film. Deposited drug composition wasdried in a lab oven at 70° C. for five minutes to provide the thin filmproduct.

Formulation 6:

TABLE 6 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition: Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine hydrochloride 0.48Active Hydroxypropyl cellulose 0.26 Film former (MW = 40,000) Hydroxypropyl cellulose 0.26 Film former (MW = 140,000) Hydroxypropylcellulose 1.57 Film former (MW = 370,000) Ethanol q.s. Solvent (orliquid carrier) Polymer matrix composition Peppermint Oil 2.06 FlavourSucralose 0.97 Sweetener Fast Emerald Green 0.13 Colour Hydroxypropylcellulose 4.7 Film former (MW = 40,000)  Hydroxypropyl cellulose 4.7Film former (MW = 140,000) Hydroxypropyl cellulose 28.29 Film former (MW= 370,000) Polyethylene oxide 56.58 Film former & (MW = 600,000)mucoadhesive Purified water q.s. Solvent (or liquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition were dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride and hydroxypropyl celluloses of the drug containingcomposition were dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 7:

TABLE 7 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition: Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine hydrochloride 0.48Active Hydroxypropyl cellulose 0.11 Film former (MW = 40,000) Hydroxypropyl cellulose 0.11 Film former (MW = 140,000) Hydroxypropylcellulose 0.63 Film former (MW = 370,000) Polyethylene oxide 1.25 Filmformer (MW = 600,000) Ethanol q.s. Solvent (or liquid carrier) Purifiedwater q.s. Solvent (or liquid carrier) Polymer matrix compositionHydroxypropyl cellulose 4.87 Film former (MW = 40,000)  Hydroxypropylcellulose 4.87 Film former (MW = 140,000) Hydroxypropyl cellulose 29.23Film former (MW = 370,000) Polyethylene oxide 58.45 Film former & (MW =600,000) mucoadhesive Purified water q.s. Solvent (or liquid carrier)

Process: All the polymers of the polymer matrix composition weredissolved in water with stirring, cast through a fixed gap onto arelease liner substrate to form a film and subsequently dried in a laboven at 70° C. for 30 minutes. Separately, dexmedetomidine hydrochlorideand polymers of the drug containing composition were dissolved in amixture of ethanol and water on a vortex mixer and then deposited (asdroplets) via volumetric pipette onto the film. Deposited drugcomposition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 8:

TABLE 8 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition: Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine hydrochloride 0.49Active Butanol q.s. Solvent (or liquid carrier) Polymer matrixcomposition Hydroxypropyl cellulose 4.98 Film former (MW = 40,000) Hydroxypropyl cellulose 4.98 Film former (MW = 140,000) Hydroxypropylcellulose 29.85 Film former (MW = 370,000) Polyethylene oxide 59.70 Filmformer & (MW = 600,000) mucoadhesive Purified water q.s. Solvent (orliquid carrier)

Process: All the polymers of the polymer matrix composition weredissolved in water with stirring, cast through a fixed gap onto arelease liner substrate to form a film and subsequently dried in a laboven at 70° C. for 30 minutes. Separately, dexmedetomidine hydrochloridewas dissolved in n-butanol on a vortex mixer and then deposited (asdroplets) via volumetric pipette onto the film. Deposited drugcomposition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 9:

TABLE 9 Dexmedetomidine deposited on the surface of a polymer matrixfilm composition: Concentration Ingredients g/100 g FunctionDrug-containing composition Dexmedetomidine 0.41 Active Sodium Chloride0.12 pH neutralizing agent Hydroxypropyl cellulose 0.26 Film former (MW= 40,000)  Hydroxypropyl cellulose 0.26 Film former (MW = 140,000)Hydroxypropyl cellulose 1.57 Film former (MW = 370,000) Ethanol q.s.Solvent (or liquid carrier) Polymer matrix composition Peppermint Oil2.06 Flavour Sucralose 0.97 Sweetener Fast Emerald Green 0.13 ColourHydroxypropyl cellulose 4.70 Film former (MW = 40,000)  Hydroxypropylcellulose 4.70 Film former (MW = 140,000) Hydroxypropyl cellulose 28.27Film former (MW = 370,000) Polyethylene oxide 56.55 Film former & (MW =600,000) mucoadhesive Purified water q.s. Solvent (or liquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition were dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidine,sodium chloride and the hydroxypropyl celluloses of the drug containingcomposition was dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 10:

TABLE 10 Dexmedetomidine deposited on the surface of a polymer matrixfilm composition: Concentration Ingredients g/100 g FunctionDrug-containing composition Dexmedetomidine 0.34 Active Sodium Chloride0.10 pH neutralizing agent Hydroxypropyl cellulose 0.22 Film former (MW= 40,000)  Hydroxypropyl cellulose 0.22 Film former (MW = 140,000)Hydroxypropyl cellulose 1.31 Film former (MW = 370,000) Ethanol q.s.Solvent (or liquid carrier) Polymer matrix composition Peppermint Oil2.07 Flavour Sucralose 0.98 Sweetener Fast Emerald Green 0.13 ColourHydroxypropyl cellulose 4.53 Film former (MW = 40,000)  Hydroxypropylcellulose 4.53 Film former (MW = 140,000) Hydroxypropyl cellulose 27.16Film former (MW = 370,000) Polyethylene oxide 54.33 Film former & (MW =600,000) mucoadhesive Glycine 3.76 Alkaline buffer Sodium hydroxide 0.32pH neutralizing agent Purified water q.s. Solvent (or liquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition were dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidine,sodium chloride and the hydroxypropyl celluloses of the drug containingcomposition were dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 11:

TABLE 11 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition: Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine hydrochloride 0.38Active Ethanol q.s. Solvent (or liquid carrier) Polymer matrixcomposition Hydroxypropyl cellulose 4.47 Film former (MW = 40,000) Hydroxypropyl cellulose 4.47 Film former (MW = 140,000) Hydroxypropylcellulose 26.83 Film former (MW = 370,000) Polyethylene oxide 53.61 Filmformer & (MW = 600,000) mucoadhesive Sodium Lactate 6.52 Acidic BufferLactic Acid 3.72 Acidic Buffer Purified water q.s. Solvent (or liquidcarrier)

Process: All the polymers and acidic buffer system of the polymer matrixcomposition were dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride was dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 12:

TABLE 12 Dexmedetomidine deposited on the surface of a polymer matrixfilm composition Concentration Concentration g/100 g g/100 g Ingredients(10 μg film) (20 μg film) Function Drug-containing compositionDexmedetomidine 0.136 0.267 Active agent hydrochloride Hydroxypropylcellulose, 0.301 0.593 Film former HPC-SSL (MW = 40,000)  Hydroxypropylcellulose 0.301 0.593 Film former (MW = 140,000) FD&C Blue #1 Granular0.002 0.004 Color Ethyl Alcohol qs qs Solvent as a solvent Polymermatrix composition Hydroxypropyl cellulose 4.803 4.768 Film former (MW =140,000) Hydroxypropyl cellulose, 4.803 4.768 Film former HPC-SSL (MW =40,000)  Hydroxypropyl cellulose 28.809 28.601 Film former (MW =370,000) Fast Emerald Green 0.129 0.128 Color Shade (NO. 06507)Sucralose, USP-NF 0.993 0.985 Sweetener Grade Peppermint Oil, NF 2.1042.089 Flavor Polyethylene oxide 57.618 57.202 Film former & (SentryPolyox Mucoadhesive WSR 205 LEO NF) (MW = 600,000) Water as a solvent qsqs Solvent

(A) Process for the Preparation of Polymer Matrix:

Polymer mixture: Polyethylene oxide and fast emerald green shade weremixed in water for at least 180 minutes at about 1400 rpm to about 2000rpm. Sucralose, hydroxypropyl cellulose (molecular weight 140K),hydroxypropyl cellulose, HPC-SSL (molecular weight 40K) andhydroxypropyl cellulose (molecular weight 370K) were added and mixed forat least 120 minutes at about 1600 rpm to 2000 rpm. Peppermint Oil wasadded to water and the resultant dispersion was then added to thepolymer mixture and mixed for at least 30 minutes. The resultant mixturewas further mixed under vacuum (248 torr) for at least for 30 minutes ata speed of 350 rpm and at temperature of 22.9° C.Coating station: A roll was placed on an unwind stand and the leadingedge was thread through guide bars and coating bars. The silicone-coatedside of the liner was placed faced up. A gap of 40 millimeters wasmaintained between the coating bars. The oven set point was adjusted to70° C. and the final drying temperature was adjusted to 85° C.Coating/drying process: The polymer mixture was poured onto the linerbetween the guide bars and the coating bars. The liner was pulled slowlythrough the coating bar at a constant speed by hand until no liquid wasremained on the coating bars. The liner was cut to approximately 12-inchlength hand sheets using a safety knife. Each hand sheet was placed on adrying board and was tapped on the corners to prevent curl duringdrying. The hand sheets were dried in the oven until the moisturecontent was less than 5% (approximately 30 minutes) and then removedfrom the drying board. The coating weights were checked against theacceptance criteria, and if met, the hand sheets were then stacked andplaced in a 34 inch×40 inch foil bag that was lined with PET releaseliner.

(B) Process for the Preparation of Deposition Solution:

FDC blue was dissolved in ethyl alcohol for at least 180 minutes.Dexmedetomidine hydrochloride was added to the ethyl alcohol solutionwith continuous stirring for 10 minutes at about 400 rpm to about 800rpm. Hydroxypropyl cellulose (40K) and hydroxypropyl cellulose (140K)were added to the mixture, and stirred for at least 30 minutes until allthe materials were dissolved.

(C) Process for the Preparation of Micro-Deposited Matrix:

The deposition solution obtained in Step (B) above was filled into apipette to the required volume (determined according to the specificdrug product strength of the final product). An appropriate amount (1.5microliters=approximately 5 micrograms) of the deposition solution weredeposited (e.g. as droplets) onto the polymer matrix obtained in Step(A), and repeated to a total of 10 times (i.e. 10 deposits/droplets)with space between each deposit to prevent merging of thedeposits/droplets and allow subsequent cutting of the film intoindividual drug-containing units. The film was initially die cut inindividual units with dimensions of 22 mm×8.8 mm containing a singledeposit of the drug-containing composition. The die cut micro-depositedmatrixes were then dried in an oven for 70° C. for 10 minutes andfurther die cut into 10 units with each unit containing a single depositof the drug-containing composition.

(D) Packaging:

Each defect-free unit was sealed individually into a foil pouch, whichwas then heat sealed. If the heat seal was acceptable the package wasconsidered as an acceptable unit for commercial use.

Other unit strengths (e.g. 40 μg, 60 μg and 80 μg films) were similarlyprepared by varying the concentrations of drug, polymers and colorantwithin the drug-containing composition. For example, the 40 μg, 60 μgand 80 μg films were prepared from drug-containing compositionscontaining, respectively, approximately 2×, 3×, and 4× the amounts ofdrug, polymers and colorant that appear in the 20 μg drug-containingcomposition described in Table 12 above.

Formulation 13:

TABLE 13 Dexmedetomidine deposited on the surface of a polymer matrixfilm composition Concentration Ingredients g/100 g FunctionDrug-containing composition Dexmedetomidine HCL 0.33 Active Ethanol q.s.Solvent (or liquid carrier) Polymer matrix composition Hydroxypropylcellulose 4.99 Film former (MW = 40,000)  Hydroxypropyl cellulose 4.99Film former (MW = 140,000) Hydroxypropyl cellulose 29.90 Film former (MW= 370,000) Polyethylene oxide 59.79 Film former & (MW = 600,000)mucoadhesive Purified water q.s. Solvent (or liquid carrier)

Process: All the polymers of the polymer matrix composition weredissolved in water with stirring, cast through a fixed gap onto arelease liner substrate to form a film and subsequently dried in a laboven at 70° C. for 30 minutes. Separately, dexmedetomidine hydrochloridewas dissolved in ethanol on a vortex mixer and then deposited (asdroplets) via volumetric pipette onto the film. Deposited drugcomposition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 14:

TABLE 14 Dexmedetomidine deposited on the surface of a polymer matrixfilm composition Concentration Ingredients g/100 g FunctionDrug-containing composition Dexmedetomidine 0.34 Active Sodium Chloride0.10 pH neutralizing agent Hydroxypropyl cellulose 0.44 Film former (MW= 140,000) Hydroxypropyl cellulose 1.31 Film former (MW = 370,000)Ethanol q.s. Solvent (or liquid carrier) Polymer matrix compositionPeppermint Oil 2.07 Flavour Sucralose 0.98 Sweetener Fast Emerald Green0.13 Colour Hydroxypropyl cellulose 4.53 Film former (MW = 40,000) Hydroxypropyl cellulose 4.53 Film former (MW = 140,000) Hydroxypropylcellulose 27.16 Film former (MW = 370,000) Polyethylene oxide 54.33 Filmformer & (MW = 600,000) mucoadhesive Glycine 3.76 Alkaline buffer Sodiumhydroxide 0.32 pH neutralizing agent Purified water q.s. Solvent (orliquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition are dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidine,sodium chloride and the hydroxypropyl celluloses of the drug-containingcomposition are dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition is dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 15:

TABLE 15 Dexmedetomidine deposited on the surface of a polymer matrixfilm composition Concentration Ingredients g/100 g FunctionDrug-containing composition Dexmedetomidine 0.34 Active Sodium chloride0.10 pH neutralizing agent Hydroxypropyl cellulose 1.75 Film former (MW= 140,000) Ethanol q.s. Solvent (or liquid carrier) Polymer matrixcomposition Peppermint Oil 2.07 Flavour Sucralose 0.98 Sweetener FastEmerald Green 0.13 Colour Hydroxypropyl cellulose 4.53 Film former (MW =40,000)  Hydroxypropyl cellulose 4.53 Film former (MW = 140,000)Hydroxypropyl cellulose 27.16 Film former (MW = 370,000) Polyethyleneoxide 54.33 Film former & (MW = 600,000) mucoadhesive Glycine 3.76Alkaline buffer Sodium hydroxide 0.32 pH neutralizing agent Purifiedwater q.s. Solvent (or liquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition are dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidine,sodium chloride and hydroxypropyl cellulose (MW=140,000) of the drugcontaining composition are dissolved in ethanol on a vortex mixer andthen deposited (as droplets) via volumetric pipette onto the film.Deposited drug composition is dried in a lab oven at 70° C. for fiveminutes to provide the thin film product.

Formulation 16:

The formulation was prepared as described in Table 16.

TABLE 16 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Hydroxypropyl cellulose 2.09 Film former (MW = 140,000)Ethanol q.s. Solvent (or liquid carrier) Polymer matrix compositionPeppermint Oil 2.06 Flavour Sucralose 0.97 Sweetener Fast Emerald Green0.13 Colour Hydroxypropyl cellulose 4.7 Film former (MW = 40,000)Hydroxypropyl cellulose 4.7 Film former (MW = 140,000) Hydroxypropylcellulose 28.29 Film former (MW = 370,000) Polyethylene oxide 56.58 Filmformer & (MW = 600,000) mucoadhesive Purified water q.s. Solvent (orliquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition are dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride and hydroxypropyl cellulose of the drug containingcomposition are dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition is dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 17:

TABLE 17 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Hydroxypropyl cellulose 0.52 Film former (MW = 140,000)Hydroxypropyl cellulose 1.57 Film former (MW = 370,000) Ethanol q.s.Solvent (or liquid carrier) Polymer matrix composition Peppermint Oil2.06 Flavour Sucralose 0.97 Sweetener Fast Emerald Green 0.13 ColourHydroxypropyl cellulose 4.7 Film former (MW = 40,000) Hydroxypropylcellulose 4.7 Film former (MW = 140,000) Hydroxypropyl cellulose 28.29Film former (MW = 370,000) Polyethylene oxide 56.58 Film former & (MW =600,000) mucoadhesive Purified water q.s. Solvent (or liquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition are dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride, and hydroxypropyl celluloses of the drug containingcomposition are dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition is dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 18:

TABLE 18 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Hydroxypropyl cellulose 0.26 Film former (MW = 40,000)Hydroxypropyl cellulose 0.26 Film former (MW = 140,000) Hydroxypropylcellulose 1.57 Film former (MW = 370,000) Ethanol q.s. Solvent (orliquid carrier) Polymer matrix composition Peppermint Oil 2.06 FlavourSucralose 0.97 Sweetener Fast Emerald Green 0.13 Colour Hydroxypropylcellulose 18.845 Film former (MW = 40,000) Hydroxypropyl cellulose18.845 Film former (MW = 140,000) Polyethylene oxide 56.58 Film former &(MW = 600,000) mucoadhesive Purified water q.s. Solvent (or liquidcarrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition are dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride, and the hydroxypropyl celluloses of the drug containingcomposition are dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition is dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 19:

TABLE 19 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Hydroxypropyl cellulose 2.09 Film former (MW = 40,000)Ethanol q.s. Solvent (or liquid carrier) Polymer matrix compositionPeppermint Oil 2.06 Flavour Sucralose 0.97 Sweetener Fast Emerald Green0.13 Colour Hydroxypropyl cellulose 18.845 Film former (MW = 40,000)Hydroxypropyl cellulose 18.845 Film former (MW = 140,000) Polyethyleneoxide 56.58 Film former & (MW = 600,000) mucoadhesive Purified waterq.s. Solvent (or liquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition are dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride, and hydroxypropyl cellulose of the drug containingcomposition are dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition is dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 20:

TABLE 20 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Hydroxypropyl cellulose 2.09 Film former (MW = 40,000)Ethanol q.s. Solvent (or liquid carrier) Polymer matrix compositionPeppermint Oil 2.06 Flavour Sucralose 0.97 Sweetener Fast Emerald Green0.13 Colour Hydroxypropyl cellulose 19.27 Film former (MW = 40,000)Polyethylene oxide 75.00 Film former & (MW = 600,000) mucoadhesivePurified water q.s. Solvent (or liquid carrier)

Process: All the polymers and other ingredients of the polymer matrixcomposition are dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride, and hydroxypropyl cellulose of the drug containingcomposition are dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition is dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 21:

TABLE 21 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Hydroxypropyl cellulose 0.26 Film former (MW = 40,000)Hydroxypropyl cellulose 0.26 Film former (MW = 140,000) Hydroxypropylcellulose 1.57 Film former (MW = 370,000) Ethanol q.s. Solvent (orliquid carrier) Polymer matrix composition Peppermint Oil 2.06 FlavourSucralose 0.97 Sweetener Fast Emerald Green 0.13 Colour Polyethyleneoxide 94.27 Film former & (MW = 600,000) mucoadhesive Purified waterq.s. Solvent (or liquid carrier)

Process: Polyethylene oxide and other ingredients of the polymer matrixcomposition are dissolved in water with stirring, cast through a fixedgap onto a release liner substrate to form a film and subsequently driedin a lab oven at 70° C. for 30 minutes. Separately, dexmedetomidinehydrochloride and hydroxypropyl celluloses of the drug containingcomposition were dissolved in ethanol on a vortex mixer and thendeposited (as droplets) via volumetric pipette onto the film. Depositeddrug composition was dried in a lab oven at 70° C. for five minutes toprovide the thin film product.

Formulation 22:

TABLE 22 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Hydroxypropyl cellulose 0.26 Film former (MW = 40,000)Hydroxypropyl cellulose 0.26 Film former (MW = 140,000) Hydroxypropylcellulose 1.57 Film former (MW = 370,000) Ethanol q.s. Solvent (orliquid carrier) Polymer matrix composition Peppermint Oil 2.06 FlavourSucralose 0.97 Sweetener Fast Emerald Green 0.13 Colour Hydroxypropylcellulose 94.27 Film former (MW = 370,000) Purified water q.s. Solvent(or liquid carrier)

Process: Hydroxypropyl cellulose and other ingredients of the polymermatrix composition are dissolved in water with stirring, cast through afixed gap onto a release liner substrate to form a film and subsequentlydried in a lab oven at 70° C. for 30 minutes. Separately,dexmedetomidine hydrochloride and hydroxypropyl cellulose of the drugcontaining composition are dissolved in ethanol on a vortex mixer andthen deposited (as droplets) via volumetric pipette onto the film.Deposited drug composition is dried in a lab oven at 70° C. for fiveminutes to provide the thin film product.

Formulation 23:

TABLE 23 Dexmedetomidine hydrochloride deposited on the surface of apolymer matrix film composition Concentration Ingredients g/100 gFunction Drug-containing composition Dexmedetomidine 0.48 Activehydrochloride Hydroxypropyl cellulose 0.26 Film former (MW = 40,000)Hydroxypropyl cellulose 0.26 Film former (MW = 140,000) Hydroxypropylcellulose 1.57 Film former (MW = 370,000) Ethanol q.s. Solvent (orliquid carrier) Polymer matrix composition Peppermint Oil 2.06 FlavourSucralose 0.97 Sweetener Fast Emerald Green 0.13 Colour Hydroxypropylcellulose 94.27 Film former (MW = 140,000) Purified water q.s. Solvent(or liquid carrier)

Process: Hydroxypropyl cellulose and other ingredients of the polymermatrix composition are dissolved in water with stirring, cast through afixed gap onto a release liner substrate to form a film and subsequentlydried in a lab oven at 70° C. for 30 minutes. Separately,dexmedetomidine hydrochloride and hydroxypropyl celluloses of the drugcontaining composition are dissolved in ethanol on a vortex mixer andthen deposited (as droplets) via volumetric pipette onto the film.Deposited drug composition is dried in a lab oven at 70° C. for fiveminutes to provide the thin film product.

Example 2

Ex-Vivo Permeation of Formulations 1 to 13 of Example 1 Compared toPRECEDEX®

Formulations 1 to 13 were evaluated on an oromucosal cell model as aproxy for drug absorption (EpiOral™; MatTek Corp., Ashland, Mass.)tissue to determine the diffusion rates and extent:

ORL-200 24-well plates (MatTek Corp) containing oral cell tissuecultures were utilized within 1 day of receipt and followingequilibration overnight in a 5% CO₂ chamber set to 37° C. and 95%relative humidity. 300 microliters of TEER-Buffer [DPBS containing Ca2+and Mg2+ and 3.6 mg/mL glucose] was added to each well within a 24-wellplate and placed in the CO₂ chamber overnight. The following morning thetissue inserts were removed from the TEER-Buffer and placed into a new24-well plate containing 300 microlitres of DPBS receiver media. Priorto dosing with Formulations 1 to 13 and Precedex®, TEER was measured oneach tissue insert to ensure viability following the equilibration.

Each insert was pre-wetted with 25 microliters DPBS prior to applyingFormulations 1 to 13 and Precedex® to the donor side of the tissueinsert, followed by an additional 25 microliters of DPBS onto the top ofeach formulation. Prior to applying Formulations 1 to 13 to the tissueinserts, Formulations 2 to 13 were die-cut to 52.65 mm² and Formulation1 was die-cut to 13.125 mm². The units were die-cut to deliver theintended dose as specified below.

The 24-well plate containing each tissue insert was returned to theincubator for the specified time and subsequently removed from theincubator following the elapsed time. The tissue inserts weretransferred to a fresh 24-well plate containing 300 microliters ofreceiver media and returned to the incubator for the additionalspecified time. 300 microliters receiver media from each well of the24-well plate was transferred to HPLC vials and stored in therefrigerator (1 day) until analyzed via UPLC/MS. This experimentalsequence was repeated for all time points.

Results: Table 24 illustrates the assay values and estimated AUCs(nanograms) of Formulations 1 to 13 and Precedex®. Table 24 furtherillustrates the disintegration time of Formulations 1, 2, 3, 7 and 13.Table 25 elucidates the diffusion of Formulations 1 to 13 and Precedex®,and FIG. 3 presents the diffusion data visually for Formulations 1 to 7,11 and Precedex®. Each of Formulations 1 to 10 and 12 performed betterthan Precedex®. For example, the rate and extent of dexmedetomidinepermeability through oral cell culture tissue from Formulations 1 to 10and 12 was in the range of 1.5 to 4.5 times the rate and extent ofdexmedetomidine permeability from Precedex®.

TABLE 24 Illustrates the assay values, disintegration time, andestimated AUCs of Formulations 1 to 13 and Precedex ® AssayDisintegration Mean Estimated Formulation (micrograms) Time Normalizedflux AUC No. Average SD (sec) (ng/cm²) (ng) 1 10.16 0.27 13 46,40210,277 2 6.718 0.58 59 43,491 5673 3 8.975 0.86 83 61,954 8274 4 6.631.01 — 5936 5 6.51 1.75 — 5886 6 10.58 NA — 8209 7 6.84 1.14 64 Mean5077 flux-103,319 8 11.9 37.5  — 10,116 9 9.37 NA — 9171 10 9.74 NA —8356 12 Assay of 1.54 Mean Estimated 20 mcg Normalized flux AUC (ng)film 20.432 of 10 mcg of 10 mcg film 46,644 film 9061 13 2.725 1.37 3543,113 2718 Precedex — — N/A 4894 (100 μg/mL) Comparative 8.402 1.20 —1924 Formulation 11

TABLE 25 Elucidates the diffusion of Formulations 1 to 13 (averagecumulative amount) and Precedex ® through an oral cell culture membrane:Time (h) 0 0.08 0.25 0.5 0.75 1 Average Formulation 1 0 1378 3355 50196245 7137 Cumulative (10 μg) amount Formulation 2 0 405 1402 2435 32623890 (ng) (10 μg) Formulation 3 0 132 1123 2615 3916 5197 (10 μg)Formulation 4 0 384 1383 2481 3384 4044 (10 μg) Formulation 5 0 279 11962340 3272 3971 (10 μg) Formulation 6 0 721 1759 3586 5197 5810 (10 μg)Formulation 7 0 348 1186 2120 2734 3354 (10 μg) Formulation 8 0 611 21223838 5439 6690 (10 μg) Formulation 9 0 801 1737 3207 4976 6120 (10 μg)Formulation 10 0 530 1091 2364 4226 5408 (10 μg) Precedex ® 0 159 7271353 2200 2893 (100 μL, 10 μg) Formulation 11 0 27.9 40 409 698 1035 (10μg) Formulation 12 0 426.5 1968.5 3679.7 5088.7 6210.5 (10 μg)Formulation 13 0 183.7 657.7 1087.8 1476.8 1809 (10 μg)Estimated AUC: Estimated area under the flux/time curve from the datausing the trapezoidal rule which confers to total drug diffused.

Example 3

Pharmacokinetics in Rabbits (Study 1)

Test Animal Description:

Species: Oryctolagus cuniculus

Initial Age: Commensurate with weight

Sex: Male

Breed: New Zealand White

Initial Body Weight: ˜1.5-4 kg

Replicates per Treatment: N=5 per dose group, total 30 rabbits(non-crossover)

Washout Interval: Minimum 3 day washout

Study design was as follows: Food was withheld from the animals for aminimum of 12 hours prior to study initiation and four hourspost-dosing. Prior to dosing, animals were weighed and assigned toexperimental groups, stratified according to body weight. Individualdoses were calculated based on body weights recorded on the day of doseadministration. Animals were anesthetized by isoflurane. Formulations 1,2, 3, 7 and 13 were administered under the tongue (SL) of the animals.Precedex® was administered via a butterfly needle followed by a 1 mLsaline flush or via straight stick in the ear vein. Blood samples werecollected pre-dosing, and at 10 minutes, 20 minutes, 30 minutes, 1 hour,2 hours, 4 hours and 8 hours post-dosing. Blood samples were stabilizedand kept cold until analysis. Bioassays were performed usingC18RP-HPLC-MS. The concentrations were measured in plasma samples usinga standard LC/MS/MS method against calibration curves with a minimum ofsix points (N=1).

Study design and PK parameters for various formulations are provided inTable 26 and Table 27 respectively:

TABLE 26 depicts the non-crossover study design: Group Test DosingAnimals Dosing Dosing Number Article Route N= Dose Conc. Volume Vehicle1 Precedex ® IV 5 1.5 4.0 0.375 0.9% μg/kg μg/mL mL/kg NaCl 2Formulation 1 SL 5 10 μg 10 μg — — 3 Formulation 2 SL 5 10 μg 10 μg — —4 Formulation 7 SL 5 10 μg 10 μg — — 5 Formulation 3 SL 5 10 μg 10 μg —— 6 Formulation 13 SL 5 10 μg 10 μg — —

TABLE 27 depicts the summary of Mean Pharmacokinetic Parameters fordexmedetomidine hydrochloride after intravenous and sublingualadministration in Male New Zealand White Rabbits with average bodyweight ranged from 2.96 to 3.34 kg: Dexmedetomidine Group 1 Group 2Group 3 Group 4 Group 5 Group 6 hydrochloride Precedex ® Formulation 1Formulation 2 Formulation 7 Formulation 3 Formulation 13 RouteIntravenous Sublingual Sublingual Sublingual Sublingual Sublingual Dose1.5 μg/kg 10 μg 10 μg 10 μg 10 μg 10 μg C_(max) (pg/mL) 738 220 112 23588.9 75.2 t_(max) (hr) 0.00 0.767 0.600 0.900 0.567 1.13 MRT_(last) (hr)0.325 1.14 1.16 1.46 1.51 1.06 AUC_(last) 161 359 149 426 151 92.6 (hr ·pg/mL) C_(max): maximum plasma concentration; t_(max): time of maximumplasma concentration; MRT_(last): mean residence time, calculated to thelast observable time point; AUC_(last): area under the curve, calculatedto the last observable time point;

Result summary: The sublingual film products (Formulations 1, 2 and 7)provided exposure levels of dexmedetomidine hydrochloride in rabbitsthat are similar to the IV route of administration, when normalized todose. Based upon mean animal mass at 3.34 kg in Group 1, the IV bolusdose administered was about 5 AUC for the IV product was 161 h·pg·mL inthe rabbit study while sublingual film products dosed at twice thestrength (10 micrograms) of the IV product gave twice the AUC (range359-426 h·pg·mL). Therefore, the delivery of dexmedetomidinehydrochloride via the films provided exposures equivalent to an IV dose.

Example 4

Pharmacokinetics in Rabbits (Study 2)

Test Animal Description:

Species: Oryctolagus cuniculus

Initial Age: Commensurate with weight

Sex: Male

Breed: New Zealand White

Initial Body Weight: ˜2.9-3.9 kg

Replicates per Treatment: N=8 per dose group, total 64 rabbits(non-crossover)

Washout Interval: Minimum 7 day washout

Blood Sampling Time Points: Pre-dose, 5, 10, 20, 30 min, 1, 2, 4, and 8hours post dose

Study design was as follows: Animals were anesthetized with isoflurane,prior to dose administration. Dosing formulations were administeredsublingually (SL) with the film or Precedex® drops placed in thesublingual space (underneath the tongue of the animal). Micro-depositedfilms in dose groups were administered sublingually with the letter ‘P’facing up (away from the mucosal tissue). Animals in the Precedex®injection dose group were anesthetized via isoflurane and Precedex with0.9% NaCl was administered via a syringe and 25 gauge needle into themarginal ear vein. The time course began with test article placement(T0). The animals were left anesthetized and in a sternal position withits head propped up for 30 minutes to ensure TA dose does not move(T0-T30). After the dosing period, the sublingual space was not wipedand the animals were recovered (T30).

Blood samples were collected from the rabbits via the ear vessel,jugular vein, or other suitable vessels via direct venipuncture, andthen placed into chilled polypropylene tubes containing K2EDTA as ananticoagulant. Samples were maintained chilled throughout processing.Blood samples were centrifuged at 4° C. and 3,000×g for 5 minutes.Plasma was then transferred to a chilled, labeled polypropylene tube,placed on dry ice, and stored in a freezer maintained at −60° C. to −80°C. pending analysis.

Plasma Samples:

Whole blood samples (˜2.0 mL) were collected from the rabbits viajugular vein or another suitable vessel at the appropriate time pointsand placed into tubes containing K2EDTA as the anticoagulant andinverted several times to mix. Blood samples were centrifuged at atemperature of 4° C. at 3000×g for 5 minutes. All samples weremaintained chilled throughout processing. The resulting plasma sampleswere transferred into polypropylene tubes and placed in a freezer set tomaintain −60 to −80° C. until shipment to the Sponsor's bioanalyticallab for analysis.

Study design and PK para meters for various formulations are provided inTable 28 and Table 29 respectively.

TABLE 28 depicts the non-crossover study design: Test Article Film Type:Formulation # Description Micro Micro Identical to formulation 12 SLfilm containing 1.47 μg deposited -1 deposited in compositiondexmedetomidine Micro Micro Identical to formulation 12 SL filmcontaining 2.94 μg deposited -2 deposited in composition dexmedetomidineMicro Micro Identical to formulation 12 SL film containing 5.88 μgdeposited -3 deposited in composition dexmedetomidine Micro MicroIdentical to formulation 12 SL film containing 8.82 μg deposited -4deposited in composition dexmedetomidine Monolith 1 Monolith Identicalto formulation 1 SL film containing 5.88 μg in compositiondexmedetomidine Monolith 2 Monolith Identical to formulation 1 SL filmcontaining 8.82 μg in composition dexmedetomidine Precedex Solution forReference SL SL solution containing (100 μg/mL) SL Drops Drops 100 μg/mLdexmedetomidine Precedex Solution for Reference 4 μg/mL dexmedetomidine(4 μg/mL) IV Injection Injection solution for IV injection Period 2Results (Minimum 7-day Washout) Precedex Solution for Reference 4 μg/mLdexmedetomidine (4 μg/mL) IV Injection Injection solution for IVinjection Precedex Solution for Reference 4 μg/mL dexmedetomidine (4μg/mL) IV Injection Injection solution for IV injection PrecedexSolution for Reference 4 μg/mL dexmedetomidine (4 μg/mL) IV InjectionInjection solution for IV injection

TABLE 29 depicts Arithmetic Mean Pharmacokinetic Results from SLAdministration of Dexmedetomidine Containing Films or Precedex ®Micro-deposited Micro-deposited Micro-deposited Micro-depositedMonolithic Monolithic film 1 film 2 film 3 film 4 film 1 film 2 SL filmSL film SL film SL film SL film SL film containing containing containingcontaining containing containing 1.47 μg 2.94 μg 5.88 μg 8.82 μg 5.88 μg8.82 μg Precedex Parameters dexmedetomidine dexmedetomidinedexmedetomidine dexmedetomidine dexmedetomidine dexmedetomidine SL Dose(μg/kg) 0.471 0.939 1.79 2.65 1.83 2.70 2.71 C_(max) (ng/mL) 0.157 0.1120.119 0.315 0.142 0.205 0.290 t_(max) (h) 1.06 1.56 0.833 1.25 0.6670.688 0.396 AUC_(last) 0.145 0.094 0.206 0.618 0.224 0.344 0.335 (hr ·ng/mL) C_(max)/Dose 0.333 0.119 0.066 0.119 0.078 0.076 0.107AUC_(last)/Dose 0.308 0.100 0.115 0.233 0.122 0.127 0.124 F % 110% 52.2%70.5% 83.4% 63.4% 45.6% 44.2% ² F % was calculated using individualanimal IV data as a crossover.

Results: The systemic exposure of dexmedetomidine following sublingualdosing showed a numeric trend for higher exposures from increased dosesfrom micro-deposited matrix films 2, 3 and 4. Micro-deposited matrixfilm 1 showed a greater than dose proportional C_(max) and AUC_(last)compared to Micro-deposited matrix films 2-4. The Monolithic films 1 and2 showed an approximate dose proportional increase in C_(max) andAUC_(last). The systemic exposure of dexmedetomidine followingsublingual dosing showed a numeric trend for higher exposures fromincreased doses from Micro-deposited matrix films 2, 3 and 4.Micro-deposited matrix films 1 showed a greater than dose proportionalC_(max) and AUC_(last) compared to Micro-deposited matrix films 2-4. TheMonolithic films 1 and 2 showed an approximate dose proportionalincrease in C_(max) and AUC_(last). The resulting F % values for the SLfilms showed higher results as compared to the Precedex SL dosing.Micro-deposited matrix films 1 and 4, which showed a 2.5 and 1.9 foldhigher F % compared to the Precedex SL dosing which could be attributedto not have crossover IV data for the animals in these groups.

Example 5

Evaluation of the Films

TABLE 30 Formulation 12 evaluated for various parameters, includingstability studies and results Parameters Specification Formulation 12Formulation 12 Strength (mcg) 10 mcg 20 mcg Appearance Green rectangularthin film Pass Pass with one blue spot Size (mm) Width: 22 mm ± 1.5 mmWidth - 22.3 mm Width - 22.2 mm Length: 8.8 mm ± 0.5 mm Length - 9.2 mmLength - 9.1 mm Assay (%) 90%-110% 105.3% 101.0% Uniformity of USP<905>Average (10): Average (10): dosage (%) Stage 1-10 of 10 specimens 105.8%99.4% (Average) AV ≤ 15 AV: 10 AV: 7 Stage 2 (if required) - 30 of 30specimens AV ≤ 25 Related Hydroxymedetomidine (1- ND ND substances(2,3-Dimethylphenyl)-1- (1H-imidazole-5-yl) ethanol) ≤1.0%N-Benzylhydroxymedeto- ND ND midine (1-(1-Benzyl-1H-imidazol-5-yl)-1-(2,3- dimethylphenyl)ethanol) ≤1.0% Ethylmedetomidine(5-[1- ND ND (2,3-Dimethylphenyl)- ethyl]-1-ethyl-1H- imidazole) ≤1.0%N-Benzylmedetomidine ND ND (1-Benzyl-5-[1-(2,3-dimethylphenyl)ethyl]-1H- imidazole) ≤1.0% N-Benzyl vinyl analog (1- NDND Benzyl-5-[1-(2,3- dimethylphenyl)vinyl]-1H- imidazole) ≤1.0% AnyUnspecified ND ND Degradant ≤1.0% Total Degradant ≤5.0%  0.0% NDDissolution (Q ≥ 80% in 15 minutes) 104.2% 102.3% Disintegration(USP<701> NMT 3 Pass Pass time Minutes) Burst strength (g) — AverageAverage (n = 3): (n = 3): 605.891 g 503.286 g Mucoadhesion (g) — Averagepeak Average peak (Average peak force force force) (n = 3): (n = 3):436.011 g 105.937 g Mucoadhesion — Average AUC Average AUC (g*sec)(Average (n = 3): (n = 3): AUC) 21.739 g*sec 4.702 g*sec Water activity≤0.75 A_(w) Average Average (n = 3): (n = 3): 0.44 0.37 Microbial LimitsTotal Aerobic Microbial <200 cfu/film <200 cfu/film Count <200 cfu/film(10 film) (10 film) Total Combined Yeast & <20 cfu/film <20 cfu/filmmolds Count <20 cfu/film (10 film) (10 film) Pseudomona aeruginosa ND NDNegative/10 units Staphylococcus aureus ND ND Negative/10 units

Stability data: Formulation (Monolithic film) and Formulation 12[Micro-deposited matrix film (60 mcg)] were packaged individually infoil pouches. The films were tested for stability by subjecting thepackaged films to temperatures of 25° C. and 40° C. After 6 months thefilms were evaluated with respect to various parameters. The results areprovided in Table 31 and Table 32.

TABLE 31 depicts stability data for the micro deposited matrix film(Formulation 12) Dexmedetomidine 60 mcg sublingual film Micro-depositedfilm stored Micro-deposited film stored at 25° C./60% RH at 40° C./75%RH 0 1 3 6 0 1 3 6 Parameters Specification month month months monthsmonth month months months Appearance Green Pass Pass Pass Pass Pass PassPass Pass rectangular film with one spot Assay 90%-110% 100.6.% 98.2%102.3% 99.4% 100.6% 102.2% 98.8% 94.3% Related Hydroxy- ND ND ND ND NDND ND ND substance medetomi- dine ≤1% N-Benzyl- ND ND ND ND ND ND ND NDHydroxy- medetomi- dine ≤1% Ethyl- ND ND ND ND ND ND ND ND medetomi-dine ≤1% N-Benzyl- ND ND ND ND ND ND ND ND medetomi- dine ≤1% N-Benzyl-ND ND ND ND ND ND ND ND vinyl Analog ≤1% Any ND ND ND ND ND ND ND NDunspecified degradant ≤1% Total    0%   0%    0%   0%    0%    0%   0%  0% degradant ≤5% Dissolution Q ≥ 80% in   97.1% 97.0%  94.8% 99.6% 97.1%  95.2% 93.8% 96.1% 15 min Disintegration USP <701> 36-169 sec59-122 sec 24-97 sec 9-36 sec 36-169 sec 20-107 sec 26-107 sec 4-31 secNMT 3 min Burst — 476.230 g 526.415 g 343.996 g 320.074 g 476.230 g413.866 g 92.133 g 57.735 g Strength Mucoadhesion Peak 510.173 g 110.010g 84.040 g 76.815 g 510.173 g 198.586 g 234.896 g 64.687 g AUC 31.307g*s 4.839 g*s 3.583 g*s 4.024 g*s 31.307 g*s 10.158 g*s 13.046 g*s 2.424g*s Water ≤0.75a_(w) 0.44 0.39 0.41 0.41 0.44 0.40 0.38 0.43 activityMicrobial Total aerobic Pass NA NA NA Pass NA NA NA limits microbial<200 cfu/film Total Pass NA NA NA Pass NA NA NA combined Yeasts andMolds <20 cfu/film Pseudomonas Pass NA NA NA Pass NA NA NA aeruginosaNegative/ 10 units Staphylococcus Pass NA NA NA Pass NA NA NA aureusNegative/ 10 units

TABLE 32 depicts stability data for the monolithic film (similar toFormulation 1-different in strength) Dexmedetomidine 60 mcg sublingualfilm Monolithic film stored Monolithic film stored at 25° C./60% RH at40° C./75% RH 0 1 2 6 0 1 2 6 Parameters Specification month monthmonths months month month months months Appearance Green Green GreenGreen Green Green Green Green rectangular rectangular rectangularrectangular rectangular rectangular rectangular rectangular thin filmthin film thin film thin film thin film thin film thin film thin filmAssay 89.4 Not done 88.0 85.6 89.4 77.0 71.8 71.9 Related substanceHydroxy- ND Not done ND 0.3 ND 0.7 0.5 0.3 medetomidineN-Benzyl-hydroxy- ND Not done ND ND ND ND ND ND medetomidineEthylmedetomidine ND Not done ND ND ND ND ND ND N-Benzyl- ND Not done NDND ND ND ND ND medetomidine N-Benzyl-vinyl ND Not done ND ND ND ND ND NDanalog Unknown A ND Not done ND ND ND ND 0.2 0.8 (Vinylmedetomidine)Total impurities 0.0 Not done ND 0.3 ND 0.7 0.7 0.8 Dissolution 87.1 Notdone ND 64.7 87.1 71.1 NA 79.4 at 15 minutes Disintegration (sec) 35.0024.33 19.00 17.00 35.00 8.33 10.00 11.30 Tensile Strength (g) 482.27472.37 662.84 428.79 482.27 18.3 14.22 14.46 Mucoadhesion (g) 1646.851004.67 1228.72 882.54 1646.85 836.64 791.90 762.82

Conclusion: Micro-deposited matrix films, as exemplified by Formulation12, are more stable than monolithic films, as exemplified by Formulation1, when stored at 25° C. and 40° C. up to 6 months.

Example 6: Phase 1, Randomized, Single-Blind, Placebo-Controlled, SingleAscending Dose Study of the Pharmacokinetics, Safety & Tolerability ofDexmedetomidine Sublingual Film (Formulation 12) in Healthy AdultVolunteers

This was a randomized, single-blind, placebo-controlled, singleascending dose pharmacokinetics, safety and tolerability study with 4dosing groups in healthy adult (18-65 years-old) males and females. Thestudy protocol was reviewed and approved by an institutional reviewboard of site(s). This study was conducted in accordance with theDeclaration of Helsinki and ICH— Good Clinical Practices (GCP).

Four (4) doses were evaluated derived from three film strengths of 10μg, 40 μg, and 60 μg: 10 μg, 20 μg (2×10 μg film), 40 μg, and 60 μg inCohort 1, 2, 3 and 4 respectively. All eligible participants, who havebeen previously screened, arrived at the clinical research unit (CRU) aday before for admission and baseline assessment. They were domiciled inthe CRU for 4 days (Day −1, 1, 2 and 3) and discharged on Day 4, andwere under medical supervision during this time. The pre-dose evaluationof all the participants was done approximately between 07:00 and 09:00hours, after an overnight fast of at least 8 hours. The participantswere given free access to drinking water until at least one hour beforedosing. A venous catheter was inserted for allowing sampling for PK. Atthe beginning of each study session, a single dose of dexmedetomidinesublingual film (Formulation 12) was administered sublingually by anunblinded staff. The dexmedetomidine sublingual film was retained in thesublingual cavity until dissolved. Evaluations were done every 5 minutesfor the first 15 minutes and then every 15 minutes to determine the timeto dissolution of the film. The ECG, BP and oxygen saturation weremonitored as per the schedule. Participants were allowed water asdesired at least 1 hour after drug administration. Standard meals wereoffered at approximately 4, 8, and 12 hours after dexmedetomidinesublingual film dosing. After plasma sampling for 24 hours followingdosing of dexmedetomidine sublingual film, the safety and tolerabilityassessments were continued until the morning of Day 4 (day ofdischarge), and were repeated again on Day 5, Day 7±1 and Day 14±2.Blood samples were collected immediately prior to dosing (baseline) and5, 10, 20, 30, 60, 90, 120, 180, 240 min. Additional blood samples werecollected at 5, 6, 8, 10, 12 and 24 hours post dose for a total of 16 PKsampling time points.

Number of Participants:

The study evaluated increasing doses of dexmedetomidine sublingual film(Formulation 12) in 4 cohorts of healthy adult participants. In thefirst two cohorts (Cohort 1 and Cohort 2), twelve (12) new participantswere enrolled per cohort, randomized in a ratio of 2:1, i.e. 8 receivingdexmedetomidine sublingual film and 4 receiving Placebo film.

Participants who received active treatment and completed the treatmentin Cohort 1, i.e. not discontinued or withdrew, received activetreatment in Cohort 3. In addition to the participants who crossed overfrom Cohort 1 to Cohort 3, six new participants were enrolled in Cohort3. Similarly, participants who received active treatment and completedthe treatment in Cohort 2, i.e. not discontinued or withdrew, receivedactive treatment in Cohort 4. In addition to the participants whocrossed over from Cohort 2 to Cohort 4, six new participants wereenrolled in Cohort 4.

Participants that dropped out receiving placebo in Cohorts 1 and 2 werereplaced by patients to receive placebo when they crossed over, i.e., inthe event that placebo participants dropped out, when crossing over fromCohort 1 to Cohort 3 or Cohort 2 to Cohort 4, additional newparticipants were added to make up the total participants to four (4) inthe placebo arms of Cohort 3 and Cohort 4.

Inclusion criteria:

-   1. Healthy males and non-pregnant/non-breast-feeding females between    18 and 65 years of age, both inclusive.-   2. Participants who were capable of giving written informed consent    for the study-   3. Participants that had body weight≥50 kg with body mass index    (BMI) in the range of 19-30 kg/m2, both inclusive-   4. Participants having physical examination and vital signs judged    to be within normal limits by the PI or designee-   5. Participants whose clinical laboratory tests (complete blood    count, blood chemistry, and urinalysis) were within normal limits or    are clinically acceptable to the PI or designee-   6. Participants who were sufficiently physically healthy to receive    a SL dose strength of dexmedetomidine sublingual film, and tolerate    drowsiness, in the opinion of the PI or designee.-   7. Participants who were fluent in English and have ability to    understand written and verbal protocol-related requirements in    English-   8. Participants who were willing and able to be confined to the CRU    for approximately 4-5 days per dosing cohort and comply with the    study schedule and study requirements.-   9. Participants that had reliable intravascular access from which to    draw blood samples.-   10. Male participants, if non-vasectomized, must agree to use a    condom with spermicide or abstain from sexual intercourse, during    the trial and for 3 months after stopping the medication.-   11. Male participant must not donate sperm starting at screening and    throughout the study period, and for 90 days after the final study    drug administration.-   12. For female participants of child-bearing potential, the    participant must be willing to practice a clinically accepted method    of birth control from at least 30 days prior to the first    administration of the study medication, during the study, and for at    least 30 days after the last dose of the study medication.-   13. For female of non-childbearing potential, the participant was    surgically sterile (i.e. has undergone hysterectomy, bilateral    oophorectomy, or tubal ligation) or in a menopausal state (at least    1 year without menses), as confirmed by FSH levels.

Exclusion criteria:

-   1. The participants with a history of allergic reaction or    intolerance to the study drug or related compounds and additives.-   2. The participants with a history of major surgery within 4 weeks    of screening-   3. The participants with a history of significant traumatic brain    injury-   4. The participants with a history of alcohol or drug dependence by    Diagnostic and Statistical Manual of Mental Disorders IV criteria    during the 6-month period prior to study entry.-   5. The participants with a history of or presence of clinically    significant psychiatric illnesses mental retardation, borderline    personality disorder, anxiety disorder, or organic brain syndrome-   6. The participants with a history of orthostatic hypotension (i.e.,    a sustained reduction of systolic BP (SBP) of at least 20 mmHg or    diastolic BP (DBP) of 10 mmHg, or both, within 3 min of standing or    head-up tilt to at least 60° on a tilt table) and high vagal tone-   7. The participants who regularly consume large amounts of    xanthine-containing substances (i.e., more than 5 cups of coffee or    equivalent amounts of xanthine-containing substances per day).-   8. The participants who were on maintenance medications that could    inhibit or induce the CYP2A6 enzyme and other medications as listed    in Appendix 15.1.-   9. The participants who had received dexmedetomidine or other    alpha-2-agonists within 1 week of the study date.-   10. The participants who had clinically significant sleep apnea or    chronic obstructive pulmonary disease or history of asthma-   11. The participants with suicidal tendency in the judgement of the    PI or designee-   12. The participants with clinical laboratory abnormalities    (including positivity for Hep B, Hep C, HIV) unless treated to    remission status.-   13. The participants with abnormal vital signs measurement in the    judgement of the PI or designee, unless treated to remission status.-   14. The participants those were enrolled in another clinical study    (e.g., laboratory or clinical evaluation) or have received an    investigational drug in the past 30 days (or within 5 half-lives of    the investigational drug, if >30 days).-   15. The participants that had a resting heart rate of <65 beats per    minute or SBP<110 mmHg or >140 mmHg or DBP<70 mmHg or >100 mmHg at    screening and pre-dosing. Have evidence of a clinically significant    12 lead ECG abnormality. Subjects that previously failed eligibility    criteria at the Screening visit or Day 1 predose due to Exclusion 15    for a resting heart rate<70 beats per minute but not <65 beats per    minute may be rescreened.-   16. The participants with an aberrant oral/buccal anatomy,    inflammation or pathology which in the opinion of the PI, may affect    SL drug administration and absorption.-   17. The participants with hepatic impairment or who have hepatic    dysfunction defined as a history of hepatic dysfunction and an    Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)    values greater than 2 times normal in the past 6 months prior to    study drug administration.-   18. The participants who had donated blood within 30 days prior to    screening or plasma donation within 7 days prior to screening.-   19. The participant who was part of the study staff personnel or    family members of the study staff personnel.

Study duration: 39-42 days.

Dosing:

Cohort 1, Cohort 2, Cohort 3 and Cohort 4 were given 10 μg, 20 μg (2×10μg films), 40 μg and 60 μg dose of dexmedetomidine sublingual films(Formulation 12) and accompanying Placebo respectively. Except for thefirst dose cohort (10 μg dose), each subsequent dose level wasauthorized after safety review of the previous dosing cohort. Dosing wasdone only once to each cohort. Dexmedetomidine sublingual film (havingdot) was different from placebo in appearance.

End Points:

1. Area under the curve (AUC0-12, AUC0-24, AUC0-∞) for 0 to 12 hours and0-24 hours post dosing for Dexmedetomidine plasma concentration, peakplasma Dexmedetomidine concentration (Cmax), time to peakDexmedetomidine concentration level (Tmax), terminal half-life (t½) ofDexmedetomidine, volume of distribution of Dexmedetomidine and clearanceof Dexmedetomidine (CL).

Results:

TABLE 33 summarizes pharmacokinetics parameters of 10 microgramsdexmedetomidine sublingual film in healthy volunteers 10 microgramsdexmedetomidine sublingual film Cmax Tmax t_(1/2) AUC_(last) AUC0-INFSubject ID (ng/L) (hr) (hr) (hr*ng/L) (hr*ng/L) 1001 37.94 1.5 2.06179.19 201.32 1002 18.27 1.00 1.17 49.45 58.27 1005 33.28 2.00 1.86116.63 140.07 1007 35.74 2.00 2.95 142.22 168.59 1009 24.15 3.02 2.70102.76 147.74 1011 30.87 1.00 2.75 114.35 138.82 1012 24.53 1.50 2.5898.28 132.11 1016 35.19 2.00 1.24 119.28 129.17 N 8 8 8 8 8 Mean 29.9961.752 2.163 115.271 139.512 SD 6.930 0.659 0.693 37.049 40.525 CV % 23.137.6 32.0 32.1 29.0 Min 18.27 1.00 1.17 49.45 58.27 Median 32.08 1.752.32 115.49 139.45 Max 37.94 3.02 2.95 179.19 201.32 Geometric 29.2141.648 2.051 109.219 132.838 Mean Geometric 25.79 39.08 37.61 38.59 37.6CV %

TABLE 34 summarizes pharmacokinetics parameters of 20 microgramsdexmedetomidine sublingual film in healthy volunteers 20 microgramsdexmedetomidine sublingual film Cmax Tmax t_(1/2) AUC_(last) AUC0-INFSubject ID (ng/L) (hr) (hr) (hr*ng/L) (hr*ng/L) 2001 0.00 0.00 0.00 200383.08 1.00 2.2 359.59 389.48 2004 65.17 2.00 1.72 259.5 279.49 200784.90 1.50 1.60 401.79 416.92 2011 70.76 2.00 1.85 309.75 337.01 201385.92 1.00 1.85 307.97 330.48 2016 42.34 3.00 1.97 198.79 225.81 210666.75 1.50 1.57 283.34 301.60 N 8 7 7 8 8 Mean 62.365 1.714 1.824265.092 285.099 SD 28.982 0.699 0.221 123.337 129.906 CV % 46.5 40.812.1 46.5 45.6 Min 0.00 1.00 1.57 0.00 0.00 Median 68.76 1.50 1.85295.66 316.04 Max 85.92 3.00 2.20 401.79 416.92 Geometric 1.601 1.813Mean Geometric 41.30 11.95 CV %

TABLE 35 summarizes pharmacokinetics parameters of 40 microgramsdexmedetomidine sublingual film in healthy volunteers 40 microgramsdexmedetomidine sublingual film Cmax Tmax AUC_(last) AUC0-INF Subject ID(ng/L) (hr) t_(1/2) (hr*ng/L) (hr*ng/L) 3011 140.25 1.00 1.78 685.15709.61 3012 78.69 2.00 2.00 427.97 461.18 3013 97.01 1.07 1.76 292.84310.29 3023 126.60 1.00 1.86 493.89 508.98 3026 135.02 1.50 1.38 482.44499.41 3032 78.06 2.00 3.38 378.67 439.85 3114 167.99 1.00 2.05 777.66806.08 3131 123.52 2.02 2.42 600.88 627.60 4001 109.62 1.00 1.82 419.51446.40 4022 204.03 1.00 1.82 664.47 704.50 4026 123.68 2.00 1.83 507.83534.00 4130 143.95 2.00 1.97 772.97 798.78 N 12 12 12 12 12 Mean 127.3681.465 2.007 542.024 570.557 SD 35.794 0.495 0.496 157.144 156.810 CV %28.1 33.8 24.7 29.0 27.5 Min 78.06 1.00 1.38 292.84 310.29 Median 125.141.28 1.85 500.86 521.49 Max 204.03 2.02 3.38 777.66 806.08 Geometric122.839 1.389 1.961 520.580 550.254 Mean Geometric 28.87 35.22 21.8130.84 29.15 CV %

TABLE 36 Evaluation of RASS Score in the First 2 Hours -Pharmacodynamics Population Parameters 10 mcg 20 mcg 40 mcg PlaceboEvaluable patients 8 8 12 14 per RASS Number of patients 2 4 4 3 whohave reached at least RASS of −1 at any time in the first 2 hours Numberof patients 1 0 0 1 who have reached a RASS of −2 at any time in thefirst 2 hours

Results: The data given in the tables 33 to 35 reflects the doseproportional pharmacokinetics. This data clearly shows thatpharmacodynamics effects lasts for 4 to 6 hours which is consistent withthe optimal treatment window. Dexmedetomidine plasma concentrationsincrease rapidly following placement of the film formulation and achieveplasma exposures to produce the pharmacodynamic effect. The half-life ofdexmedetomidine sublingual film Formulation 12 is comparable to IVdexmedetomidine. FIG. 4 reflects the mean dexmedetomidine plasma logconcentration vs. time for 10, 20 and 40 mcg of dexmedetomidinesublingual film (semi-log scale) and clearly demonstrates that 70-80% ofthe mean concentrations were achieved before 1 hour of dexmedetomidinefilm administration. Further data revealed that dexmedetomidinesublingual thin film (Formulation 12) was safe and well tolerated withno serious adverse events. All adverse events were transient and mild(below grade 2) except moderate headache (2 in placebo group), moderatesystolic/diastolic decrease (1 in placebo), and moderate dizziness (2subjects in 40 μg group with orthostatic changes). Only drowsiness anddizziness were seen at rates greater than 1-2 subjects per group, thusthere is no clear sedative effect. vs. placebo. The most common adverseevent seen was drowsiness, observed at rates similar to placebo. Lowerrates of dizziness were reported in all groups, and was greater thanplacebo only for 40 μg group. The study demonstrated that meancardiovascular changes were not clinically meaningful and the maximumtolerated dose as not reached. The data is further depicted in FIGS. 5to 11.

Example 7: A Phase Ib Multicenter, Randomized, Double-Blind,Placebo-Controlled, Multiple Ascending Dose Study to Determine Efficacy,Pharmacokinetics and Safety of Dexmedetomidine Sublingual Film inAgitation Associated with Schizophrenia

Adaptive evaluation of escalating dose regimens of 20 μg, 60 μg and 120μg were performed for the first stage, with an option to test adifferent dose should a safety or tolerability signal be observed. Maleand female adults with acute agitation associated with schizophrenia,schizoaffective disorder, or schizophreniform disorder were enrolled ineach cohort. Investigators chose to repeat the 20 μg dose 1 hour afterinitial administration.

Arms and Interventions (Table 37)

Arms Intervention Placebo Comparator: Placebo Drug: Placebo filmSublingual Film with no active Placebo film for dexmedetomidine drug;single administration hydrochloride Experimental: 20 micrograms Drug:Sublingual film containing Sublingual Film containing 20 dexmedetomidinehydrochloride micrograms dexmedetomidine; Administration: Sublingualfilm single administration with containing dexmedetomidine for repeatdose after 1 hour the treatment of agitation associated withSchizophrenia Experimental: 60 micrograms Drug: Sublingual filmcontaining Sublingual Film containing 60 dexmedetomidine hydrochloride.micrograms dexmedetomidine; Administration: Sublingual film singleadministration containing dexmedetomidine for the treatment of agitationassociated with Schizophrenia Experimental: 120 micrograms Drug:Sublingual film containing 2 Sublingual Films, each dexmedetomidinehydrochloride. containing 60 micrograms Administration: Sublingual filmdexmedetomidine; single containing dexmedetomidine for administration of2 films the treatment of agitation associated with Schizophrenia

Blinded periodic safety data reviews were undertaken on an ongoing basisto review all subjects assigned, dosed and as data became available.Dose escalation was allowed unless a safety or tolerability issue becameevident upon periodic regular safety review. Each site was assigned asmall number of each dose cohort in an escalating although blindedfashion such that a given cohort was balanced between sites to accountfor subject-site and inter-rater variability. Patients at a site wereassigned to the lowest dose cohort with subsequent patients assigned toincreasing doses. This sequential escalating adaptive enrollment ensuressubject safety; the lowest dose cohort completes accrual first, higherdose cohorts complete last. Should a subject not respond, theinvestigator might repeat the dose such that the subject receives asecond administration (and no further) of the same randomized dosethereby testing the safety/efficacy of receiving two doses separated by1 hour which approximates dosing before initiating the next dose levelcohort. Sequential accrual of subjects in the high dose cohort enablesmore rapid discontinuation of dosing, exposing only a minimum number ofsubjects, should dose-limiting safety or tolerability be observed.Further, based upon blinded analyses integrating PK, exposure and thesafety/tolerability of all subjects and doses, the dose regimen may bealtered (e.g. repeated dosing may be discontinued or allowed only afteran elapsed time), or different dose may be selected to test thehypothesis that a (typically lower) dose regimen is better tolerated.

Eligible subjects were randomized to dexmedetomidine sublingual film(Formulation 12) or Placebo. At the beginning of each study session, asingle dose of dexmedetomidine sublingual film (Formulation 12) wasself-administered sublingually by the patient, after training with aplacebo film and under the supervision of an unblinded staff who had notparticipated in evaluation of safety or efficacy.

Dexmedetomidine sublingual film (Formulation 12) was retained in thesublingual cavity until dissolved. Participants were evaluated for localirritation around the area where the film was placed. Efficacy andsafety assessments were conducted periodically before and after dosing.If reduction in PEC is less than or equal to 40% one hour after thefirst administration, the investigator may request a second dose ofdexmedetomidine sublingual film be administered (of the same randomizeddose) with an additional PEC assessment completed at 1.5 hourspost-dose. Should the patient's situation warrant it, standard of caretreatment may be initiated, e.g. after the 4 hours assessments arecompleted.

Stage 1: In each cohort twenty-seven (27) new participants wereenrolled, randomized 2:1 Dexmedetomidine sublingual film: Placebo film,i.e. 18 received dexmedetomidine sublingual film and 9 received placebofilm. Three doses were initially planned (total of 81 subjects). Adifferent or additional dose may be tested based on ongoing safetyreviews. At the conclusion of Stage 1, two doses that describe a safeand effective range (High and Low) will selected based upon blindedreview of the overall clinical safety, tolerability, adverse effects andPK observed during dosing.

Stage 2: In order to more accurately estimate the range of safetytolerability and calming effects observed upon exposing greater numbersof subjects, an additional 120 subjects are enrolled in a double blindplacebo controlled parallel group sequential 3-arm design testing eachof two identified effective doses or placebo (randomized 1:1:1High:Low:placebo with 40 subjects per arm; total 120 subjects in Stage2; Study total of approximately 201 subjects).

Vital Signs and ECG with rhythm strip are measured as per schedule ofassessments, prior to any PK assessments. Participants are allowed wateras desired 30 minutes after completion of dosing. Standard meals may beoffered beginning 1 hour after dexmedetomidine sublingual film dosing.Safety and tolerability assessments are continued until the morning ofDay 3 (day of discharge) and will be repeated again on Day 7(+2).

Approximately 4 mL of venous blood (to obtain a minimum of 1.2 mLplasma) will be taken into K2-EDTA tubes at set time intervals for thedetermination of plasma concentrations of study drug (or Placebo). ThePK plasma samples should be collected within 5 minutes of the scheduledsampling time on Day 1. Blood samples will be collected per Table 3-1Schedule of Events.

Number of subjects (planned): An estimated 201 subjects (81 in stage 1and 120 in stage 2) are enrolled at approximately 12-20 study sites inthe United States.

Diagnosis and Main Criteria for Eligibility:

Inclusion Criteria:

-   1. Male and female patients between the ages of 18 to 65 years,    inclusive.-   2. Patients who have met DSM-5 criteria for schizophrenia,    schizoaffective, or schizophreniform disorder.-   3. Patients who are judged to be clinically agitated at Baseline    with a total score of ≥14 on the 5 items (poor impulse control,    tension, hostility, uncooperativeness, and excitement) comprising    the PANSS Excited Component (PEC).-   4. Patients who have a score of ≥4 on at least 1 of the 5 items on    the PEC.-   5. Patients who read, understand and provide written informed    consent.-   6. Patients who are in good general health prior to study    participation as determined by a detailed medical history, physical    examination, 12-lead ECG with rhythm strip, blood chemistry profile,    hematology, urinalysis and in the opinion of the Principal    Investigator.-   7. Female participants, if of child-bearing potential and sexually    active, and male participants, if sexually active with a partner of    child-bearing potential, who agree to use a medically acceptable and    effective birth control method throughout the study and for one week    following the end of the study. Medically acceptable methods of    contraception that may be used by the participant and/or his/her    partner include abstinence, birth control pills or patches,    diaphragm with spermicide, intrauterine device (IUD), condom with    foam or spermicide, vaginal spermicidal suppository, surgical    sterilization and progestin implant or injection. Prohibited methods    include: the rhythm method, withdrawal, condoms alone, or diaphragm    alone.

Exclusion Criteria:

-   1. Patients with agitation caused by acute intoxication, including    positive identification of alcohol by breathalyzer or    non-prescription drugs (with the exception of THC) during urine    screening.-   2. Patients treated within 4 hours prior to study drug    administration with benzodiazepines, other hypnotics or oral or    short-acting intramuscular antipsychotics.-   3. Treatment with alpha-1 noradrenergic blockers (terazosin,    doxazosin, tamsulosin, and alfuzosin, and prazocin) or other    prohibited medications.-   4. Patients with significant risk of suicide or homicide per the    investigator's assessment, or any suicidal behaviour in last 6    months prior to screening.-   5. Female patients who have a positive pregnancy test at screening    or are breastfeeding.-   6. Patients who have hydrocephalus, seizure disorder, or history of    significant head trauma, stroke, transient ischemic attack,    subarachnoid bleeding, brain tumor, encephalopathy, meningitis,    Parkinson's disease or focal neurological findings.-   7. History of syncope or other syncopal attacks, current evidence of    hypovolemia, orthostatic hypotension, a screening heart rate of <55    beats per minutes or systolic blood pressure<110 mmHg or diastolic    BP<70 mmHg.-   8. Patients with laboratory or ECG abnormalities considered    clinically significant by the investigator or qualified designee    [Advanced heart block (second-degree or above atrioventricular block    without pacemaker), diagnosis of Sick sinus syndrome] that would    have clinical implications for the patient's participation in the    study.-   9. Patients with serious or unstable medical illnesses. These    include current hepatic (moderate severe hepatic impairment), renal,    gastroenterologic, respiratory, cardiovascular (including ischemic    heart disease, congestive heart failure), endocrinologic, or    hematologic disease.-   10. Patients who have received an investigational drug within 30    days prior to the current agitation episode.-   11. Patients who are unable to use the sublingual film or considered    by the investigator, for any reason, to be an unsuitable candidate    for receiving dexmedetomidine; e.g. patients with a history of    allergic reactions to dexmedetomidine.

Test Product, Dose, and Mode of Administration:

Dexmedetomidine sublingual film (Formulation 12) is tested in a small,solid-dose film formulation, approximately 193.6 mm² in area and 0.7 mmthick, designed to completely dissolve in the SL space within 2-3minutes.

Reference Therapy, Dosage and Mode of Administration:

Matching placebo films to be taken sublingually as described above.

Duration of Treatment: 1 day

Criteria for Evaluation

Efficacy assessment: Assessment of drug effects on acute agitation doneby the Positive and Negative Syndrome Scale-Excited Component (PEC). ThePEC comprises 5 items associated with agitation: poor impulse control,tension, hostility, uncooperativeness, and excitement; each scored 1(minimum) to 7 (maximum). The PEC, the sum of these 5 subscales, thusranges from 5 to 35.

Overall agitation and sedation will be evaluated with theAgitation-Calmness Evaluation Scale (ACES), where 1 indicates markedagitation; 2—moderate agitation; 3—mild agitation; 4—normal behavior;5—mild calmness; 6—moderate calmness; 7—marked calmness; 8—deep sleep;and 9—unarousable. The change in agitation in response to treatment willalso be measured by the Clinical Global Impressions-Improvement (CGI-I).CGI-I scores range from 1 to 7: 0=not assessed (missing), 1=very muchimproved, 2=much improved, 3=minimally improved, 4=no change,5=minimally worse, 6=much worse, 7=very much worse.

Safety and tolerability assessments: AEs, clinical laboratory tests, ECGwith rhythm strip, and vital signs are monitored for tolerabilityassessment. All observed and volunteered AEs are recorded. Therelationship of AEs to the study drugs are graded as not related,unlikely/remotely related, possibly related, probably related ordefinitely related by the investigators. Vital signs including systolicblood pressure (SBP), diastolic blood pressure (DBP), and heart rate aremeasured prior to the PK blood samples. The application site of the SLpreparation (buccal mucosa) is inspected for any signs of localirritation.

Additional Assessments:

-   -   Demographic Data    -   Medical History    -   Prior and Concomitant Medication    -   Physical Examination    -   Pregnancy

Efficacy Analyses: The primary efficacy endpoint for Stage 1 is theproportion of subjects at each dose that achieve a 40% reduction in PECat 2 hr. The primary efficacy endpoint for Stage 2 is the absolutechange from baseline in the PEC total score at 2 hr.

Sample Size Determination: The study is not powered for detectingstatistically significant differences in efficacy parameters. However,cohorts of up to 27 subjects (2:1 ratio of dexmedetomidine sublingualfilm:placebo) are sufficient to characterize the safety, tolerabilityand PK profile in Stage 1. In Stage 2, cohorts of 40 subjects areenrolled (40 on high dexmedetomidine sublingual film dose, 40 on lowdexmedetomidine sublingual film dose, 40 on placebo).

Results of Stage 1

TABLE 38 Summary statistics of PK parameter estimates Dose Tmax Cmax t½AUClast AUCINF_obs Cohort (ug) Redose Statistics (hr) (ng/L) (hr)(hr*ng/L) (hr*ng/L) 1 20 No N 10 10 9 10 9 Mean 1.895 39.898 3.313171.639 246.444 SD 0.813 15.019 1.021 57.654 63.994 CV % 42.9 37.6 30.833.6 26.0 Min 1.00 14.07 2.12 57.43 145.57 Median 1.74 37.02 3.17 180.09241.74 Max 4.02 69.05 5.36 264.45 332.10 Geometric 1.778 37.157 3.183160.056 238.688 Mean Geometric 36.99 43.89 30.51 45.41 27.86 CV % 1 20Yes N 8 8 7 8 7 Mean 2.935 96.589 2.946 586.103 499.866 SD 2.077 36.9540.857 556.166 226.187 CV % 70.8 38.3 29.1 94.9 45.2 Min 1.83 49.87 1.81230.06 294.47 Median 2.31 104.54 3.01 444.23 520.36 Max 8.03 138.69 4.021912.52 939.05 Geometric 2.578 89.711 2.833 453.552 461.828 MeanGeometric 50.30 44.50 31.46 78.77 44.05 CV % 2 60 No N 18 18 17 18 17Mean 1.528 139.589 2.861 681.542 792.552 SD 0.689 47.223 1.381 482.593525.000 CV % 45.1 33.8 48.3 70.8 66.2 Min 0.98 73.42 1.48 265.85 293.67Median 1.50 131.78 2.36 503.20 616.68 Max 3.95 253.14 6.98 2072.022195.38 Geometric 1.429 132.558 2.640 576.084 673.986 Mean Geometric36.00 33.88 40.27 60.19 60.92 CV %

TABLE 39 Individual and summary statistics of PK parameter estimates ofdexmedetomidine in plasma Dose Tmax Cmax t½ AUClast AUCINF_obs Cohort(ug) Redose Subject ID (hr) (ng/L) (hr) (hr*ng/L) (hr*ng/L) 1 20 No01-001 1.50 35.54 4.10 224.01 326.88 01-002 1.50 38.55 3.68 182.58241.74 01-010 1.00 59.82 2.12 104.40 145.57 01-026 4.02 14.07 57.4307-015 1.53 33.41 5.36 177.60 299.81 07-030 2.00 34.31 2.29 176.11203.81 10-027 2.00 35.38 3.64 184.37 255.41 23-016 1.48 69.05 2.95264.45 332.10 23-018 1.97 40.37 3.17 154.62 186.40 23-020 1.95 38.492.51 190.81 226.26 N 10 10 9 10 9 Mean 1.895 39.898 3.313 171.639246.444 SD 0.813 15.019 1.021 57.654 63.994 CV % 42.9 37.6 30.8 33.626.0 Min 1.00 14.07 2.12 57.43 145.57 Median 1.74 37.02 3.17 180.09241.74 Max 4.02 69.05 5.36 264.45 332.10 Geometric 1.778 37.157 3.183160.056 238.688 Mean Geometric 36.99 43.89 30.51 45.41 27.86 CV % 1 20Yes 01-009 2.00 130.44 3.94 662.46 939.05 01-013 2.00 122.23 2.73 486.82563.33 05-007 2.50 49.87 4.02 230.06 334.28 05-008 2.12 66.64 2.00272.47 304.52 05-021 2.50 86.86 3.10 410.74 543.04 05-023 2.50 52.293.01 236.04 294.47 05-024 8.03 138.69 1912.52 07-028 1.83 125.70 1.81477.73 520.36 N 8 8 7 8 7 Mean 2.935 96.589 2.946 586.103 499.866 SD2.077 36.954 0.857 556.166 226.187 CV % 70.8 38.3 29.1 94.9 45.2 Min1.83 49.87 1.81 230.06 294.47 Median 2.31 104.54 3.01 444.23 520.36 Max8.03 138.69 4.02 1912.52 939.05 Geometric 2.578 89.711 2.833 453.552461.828 Mean Geometric 50.30 44.50 31.46 78.77 44.05 CV % 2 60 No 01-0441.00 93.67 3.10 442.23 558.81 01-047 1.00 73.42 2.23 265.85 293.6701-055 1.50 113.35 2.87 474.46 562.60 01-056 1.50 154.79 1.48 413.53428.64 03-036 1.55 83.52 1.62 347.11 369.07 05-050 1.00 121.52 1.86352.24 377.98 05-052 1.45 105.84 2.36 330.30 369.14 06-033 1.45 253.142.27 737.87 834.44 06-034 1.53 206.42 2.35 887.27 1007.71 06-041 2.07144.27 6.98 1714.29 1882.10 06-043 1.02 186.40 2.53 748.96 877.63 07-0480.98 201.12 2.91 874.85 1064.08 08-046 2.00 93.22 346.61 09-042 3.95146.17 5.43 2072.02 2195.38 10-032 1.50 136.25 3.40 650.22 807.14 10-0351.50 127.27 2.78 519.54 616.68 10-039 1.00 144.93 2.27 603.55 691.0010-045 1.50 127.30 2.19 486.85 537.29 N 18 18 17 18 17 Mean 1.528139.589 2.861 681.542 792.552 SD 0.689 47.223 1.381 482.593 525.000 CV %45.1 33.8 48.3 70.8 66.2 Min 0.98 73.42 1.48 265.85 293.67 Median 1.50131.78 2.36 503.20 616.68 Max 3.95 253.14 6.98 2072.02 2195.38 Geometric1.429 132.558 2.640 576.084 673.986 Mean Geometric 36.00 33.88 40.2760.19 60.92 CV %

Tables 38 and 39 and FIGS. 17 and 18 illustrate that the median Tmaxranges from 1.5-2.3 hours for different dose levels. Further, exposureis increasing with increasing dose from 20 to 60 mcg in a proportionalmanner. The redosing of 20 mcg after 1 hr in Cohort 1 led to 2.5-foldincrease in the geometric mean of Cmax and in AUC.

FIGS. 19 and 20 show that in Cohort 3, a 120 mcg dose resulted in asignificant decrease in the PEC Score, compared with pooled placebogroup. Notably, the decrease in PEC Score in 120 mcg is differentiatedfrom the pooled placebo group at 0.5 hr and is maintained throughout thecourse of the measurement (6 hr).

Example 8: Clinical Study of the Efficacy (Sedation and Anti-Agitation),Pharmacokinetics and Safety of Dexmedetomidine Infused Intravenously inSubjects Suffering from Schizophrenia

A Key Objective of the study was to determine the optimal intravenous(IV) dose of dexmedetomidine hydrochloride in the target population interms of efficacy and safety to achieve arousable sedation (RASS of −1)which can be reversed by verbal stimulation. When this goal was achievedin each participant, the IV infusion of dexmedetomidine hydrochlorideceased. Another Key Objective of the study was to determine thereduction in the level of agitation, as determined by their PEC score,at the doses to achieve a RASS of −1.

In addition, the following Secondary Objectives were:

Determine how rapidly the drug can be administered up to the total doseneeded to achieve RASS−1.

Determine how long the calming effect persists after discontinuation ofstudy drug administration.

Determine whether any adverse effects on blood pressure, heart rate, orrespiratory drive occurs before or coincident with the achievement ofPrimary Objective. Stopping rules for blood pressure and heart rate,indicating a clinically significant event, are:

drop in systolic BP<90 mm of Hg.

drop in diastolic BP<60 mm of Hg

drop below 50 beats per minute

Participants were provide written informed consent before any studyrelated procedures were performed. All participants were screened forinclusion and exclusion criteria. The participants were admitted to thesite at screening (Day −1), the day before the infusion. Baselineassessments were performed on Day −1, as well as on the day of infusion(Day 1). The participants were on Day 1 prepared for the infusion,infused for up to 3 hours and monitored for resolution of sedation andany decreases in blood pressure or heart rate which met stoppingcriteria. The participants were not discharged from the research unituntil three hours after resolution of any reduction in the level ofarousal (e.g., RASS−1) and/or resolution of any decrease in bloodpressure or heart rate meeting stopping criteria. The PrincipalInvestigator had discretion to keep the participant overnight at thesite the evening of Day 1 for extended monitoring and then dischargehome the participant on Day 2 if the Principal Investigator or designeedetermined that the participant has returned to their baseline state.

The study population included 14 participants, 10 active and 4 placebo.Patients 5, 7, 8 and 9 received placebo. Patients 1, 2, 3, 4, 11, 12,14, 16, 17, 18 were infused with intravenous dexmedetomidinehydrochloride, starting at a rate of 0.2 mcg/kg/hr, and rising by 0.1mcg/kg/hr every 30 minutes until stopping criteria were reached up or toa maximum duration of 3 hours. Participants randomized to placeboreceived a matching intravenous infusion of placebo solution.

TABLE 40 Study Treatments Treatment Formulation FrequencyDexmedetomidine Precedex ® Continuous infusion, hydrochloride incrementevery 30 minutes Placebo Normal Saline Continuous infusion

Once the participant was drowsy (RASS−1), the infusion was stopped. Themaximum total dose administered was 1.6 mcg/kg/hr, when either thedesired level of sedation was achieved or the maximum allowable decreasein either systolic or diastolic blood pressure or heart rate occurred.

The participants were continuously monitored during the study by thesite personnel, including monitoring blood pressure and heart rate.Intermittent electrocardiograms were taken from the start of theinfusion through resolution of the sedation and/or any adverse effectson blood pressure or heart rate.

Whenever the above stopping criteria was met, the site stopped theinfusion and the site continued to monitor the participant's vital signsevery 15 minutes until the participant has reached their baselineparameters or in the judgment of the principal investigator theparticipant has reached a stable and acceptable level of blood pressureand heart rate. Return to baseline parameters is defined as BP fallingwithin 15 mm of Hg of baseline reading prior to drug administration orHR falling within 10 beats per minute of baseline reading prior to drugadministration.

In the event the investigator deemed the fall in blood pressure or heartrate to be clinically significant, suitable remedial drugs could beadministered in addition to termination of the dexmedetomidinehydrochloride infusion, based on investigator's judgement.

Adverse events (AEs), including serious adverse events (SAEs), wereassessed, recorded, and reported in accordance with FDA guidance. Shouldany SAE occur, the study would be stopped until a cause for the SAE wasdetermined.

Efficacy Assessment:

(1) Richmond Agitation Sedation Scale (RASS): The desired endpoint washow rapidly drowsiness (RASS−1) could be achieved without causingchanges in heart rate or blood pressure greater than that specified bythe protocol. The study also monitored how long the participant remainedat that level of sedation; sedation was considered resolved when theparticipant was awake and spontaneously responding.

(2) PANS S: Change from baseline for mildly agitated patients

(3) Clinical Global Impression of Improvement (CGI-I) (NationalInstitute of Mental Health 1976) ranging from 1 (very much improved) to7 (very much worse) compared with baseline. Each participant was rated,based on the severity of agitation, at 15 and 30 minutes for every doseinfusion, at the endpoint, and at the time the participant returned tobaseline (in terms of level of arousal). CGI-I focused on the severityof agitation rather than the severity of the illness.

(4) After the infusion was stopped, the participants were judged for thesuitability for discharge by the principal investigator or designee aswitnessed by a return to their baseline level of alertness and awarenesswith no impairment in balance, gait, and reaction time as determined bythe principal investigator or designee.

Results

(A) Efficacy Study

RASS (Richmond Agitation-Sedation Scale)

9 out of 10 patients in the treatment arm (subjects 1-3, 11, 12, 14, and16-18) achieved a RASS score of at least −1, while no patients in theplacebo arm (subjects 5, and 7-9) experienced meaningful sedation (seeFIG. 12 and Table 41).

TABLE 41 Depicts the RASS score of Schizophrenia patients receivinginfusion of dexmedetomidine hydrochloride and normal saline Infu- RASSvalues after infusion start sion Patient No. (min- 1 2 3 4 5 7 8 9 11 1214 16 17 18 utes) T T T T P P P P T T T T T T 0 1 3 1 1 1 1 1 1 1 1 1 11 0 15 −2 −1 30 0 0 0 1 1 1 1 0 0 0 0 0 45 0 −1 60 0 −1 0 1 1 0 1 0 0 00 75 −1 −1 −1 −1 90 0 1 0 0 1 0 105 120 0 0 0 0 1 −1 135 0 150 0 0 0 1165 180 0 0 0 1 T—treatment arm; P—placebo armPEC (PANSS Excitement Component)

9 out of 10 patients in the treatment arm (subjects 1-4, 11, 12, 14, 16and 17) had agitation reduced to a minimum (as measured by a PEC scoreof 7 or below) (see Table 42 and FIG. 13).

TABLE 42 Depicts the PEC data of schizophrenia patients receivinginfusion of dexmedetomidine and normal saline PEC values after infusionstart Patient No. Time 1 2 3 4 5 7 8 9 11 12 14 16 17 18 (Mins) T T T TP P P P T T T T T T 0 9 16 12 9 11 12 9 13 13 13 10 10 10 15 5 13 12 910 12 9 13 13 13 9 9 8 30 12 10 8 9 9 8 12 11 13 6 6 7 45 11 7 8 9 8 812 9 10 6 6 5 60 9 6 7 8 8 8 13 9 10 5 7 75 7 7 8 8 7 11 7 8 5 5 90 7 79 7 11 6 105 7 8 8 7 10 5 120 7 8 8 7 10 135 7 8 7 7 9 150 8 7 7 9 165 88 7 9 180 8 8 7 10 T—treatment arm; P—placebo arm(B) Pharmacokinetic Study: (PK Study)

The level of dexmedetomidine in the plasma of patients was also measuredover the time of infusion. The results are tabulated in Table 43. Themaximum dexmedetomidine concentrations in schizophrenic patients(C_(max)) ranged from about 22.45 pg/ml to about 406.3 pg/ml. Time toreach C_(max) ranged from about 15 minutes to about 105 minutes. Meaninfusion rate is 0.36 mcg/kg/hr with the maximum rate ranging from about0.2 mcg/kg/hr to about 0.6 mcg/kg/hr (see FIGS. 14, 15 and 16).

TABLE 43 depicts the plasma concentrations (pg/mL) of schizophreniapatients at different timepoints during the infusion of dexmedetomidinehydrochloride and normal saline Plasma level concentration (picogram/ml)Time 1 2 3 4 5 7 8 9 11 12 14 16 17 18 (Mins) T T T T P P P P T T T T TT 0 BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ 15 22.45 BLQ BLQBLQ BLQ BLQ 41.0 BLQ BLQ 2.56 15.87 48.36 30 14.72 BLQ BLQ BLQ BLQ BLQBLQ BLQ 62.91 44.87 52.66 15.59 BLQ 54.53 45 BLQ BLQ BLQ BLQ BLQ BLQ124.07 50.51 46.53 41.17 39.93 60 BLQ BLQ BLQ BLQ BLQ 150.47 108.6 406.367.88 75 BLQ BLQ BLQ BLQ BLQ 158.54 72.26 90 44.3 BLQ BLQ BLQ BLQ 237.83105 BLQ BLQ BLQ BLQ 267.3 120 BLQ BLQ BLQ BLQ 135 BLQ BLQ BLQ BLQ 150BLQ BLQ BLQ BLQ 165 BLQ BLQ BLQ BLQ 180 BLQ BLQ BLQ BLQ Total 19 75 60149 180 180 180 179 68 103 64 66 36   30 duration of infusion (Mins)*BLQ—below limit of quantification T—Treatment; P—Placebo

Discussion: The administration of dexmedetomidine hydrochloride by theIV route produced a >=50% reduction in PEC score in a total of 7 of 10subjects, with one subject (Patient 1) responding at a Cmax of 22 pg/mL.5 of 10 subjects (Patients 1, 2, 3, 16 and 17) exhibited a 40% reductionin PEC score at a Cmax of =<72 pg/mL. The good response rates at theseplasma exposure levels indicates that sublingual dexmedetomidinehydrochloride administration at similar or higher Cmax exposure levelswill achieve good anti-agitation effects. As demonstrated in Example 6above, sublingual dexmedetomidine hydrochloride administered to healthyvolunteers produced good plasma exposure levels at doses of 10, 20 and40 micrograms, indicating that such doses would be suitable forobtaining good anti-agitation effects (e.g. as measured by a reductionin PEC score) in agitated subjects, including subjects withschizophrenia, without also producing clinically meaningful detrimentaleffects on blood pressure and/or heart rate.

What is claimed is:
 1. A self-supporting, dissolvable, mucoadhesive filmcomprising: (i) dexmedetomidine or a pharmaceutically acceptable saltthereof; (ii) a first water-soluble hydroxypropyl cellulose polymerhaving a molecular weight of about 40,000 daltons; (iii) a secondwater-soluble hydroxypropyl cellulose polymer having a molecular weightof about 140,000 daltons; (iv) a third water-soluble hydroxypropylcellulose polymer having a molecular weight of about 370,000 daltons;and (v) a water-soluble polyethylene oxide polymer having a molecularweight of about 600,000 daltons; wherein: the only polymers present inthe film are water-soluble hydroxypropyl cellulose and water-solublepolyethylene oxide polymers; said first water-soluble hydroxypropylcellulose polymer having a molecular weight of about 40,000 daltons ispresent at about 3% to about 15% w/w of the total film weight; saidsecond water-soluble hydroxypropyl cellulose polymer having a molecularweight of about 140,000 daltons is present at about 3% to about 8% w/wof the total film weight; and said third water-soluble hydroxypropylcellulose polymers having a molecular weight of about 370,000 daltons ispresent at about 10% to about 50% w/w of the total film weight; saidwater-soluble polyethylene oxide polymer having a molecular weight ofabout 600,000 daltons is present at about 40% to about 70% w/w of thetotal film weight; the polymers in (ii), (iii), (iv) and (v) abovetogether form a single layer film substrate; and dexmedetomidine or apharmaceutically acceptable salt thereof is present on one surface ofsaid single layer film substrate.
 2. The film according to claim 1,wherein said dexmedetomidine or a pharmaceutically acceptable saltthereof is dexmedetomidine hydrochloride which is present at a weightratio of about 0.05 micrograms to about 3 micrograms for each 100micrograms of total weight of film.
 3. A self-supporting, dissolvable,mucoadhesive film for buccal administration consisting of: (a) acomposition comprising: (i) dexmedetomidine hydrochloride; (ii)hydroxypropyl cellulose having a molecular weight of about 40,000daltons; and (iii) hydroxypropyl cellulose having a molecular weight ofabout 140,000 daltons; and (b) a film substrate comprising: (i)hydroxypropyl cellulose having a molecular weight of about 40,000daltons; (ii) hydroxypropyl cellulose having a molecular weight of about140,000 daltons; (iii) hydroxypropyl cellulose having a molecular weightof about 370,000 daltons; and (iv) polyethylene oxide having a molecularweight of about 600,000 daltons; wherein the only polymers present inthe film are water-soluble hydroxypropyl cellulose and water-solublepolyethylene oxide polymers; hydroxypropyl cellulose having a molecularweight of about 40,000 daltons is present at about 3% to about 15% w/wof the total film weight; hydroxypropyl cellulose having a molecularweight of about 140,000 daltons is present at about 3% to about 8% w/wof the total film weight; hydroxypropyl cellulose having a molecularweight of about 370,000 daltons is present at about 10% to about 50% w/wof the total film weight; and polyethylene oxide having a molecularweight of about 600,000 daltons is present at about 40% to about 70% w/wof the total film weight; and the composition of part (a) is present onthe surface of the film substrate (b).
 4. The film according to claim 3,wherein the composition of part (a) constitutes about 0.1% to about 10%w/w of the total film weight.
 5. The film according to claim 3, whereindexmedetomidine hydrochloride is present at about 0.05% to about 3% w/wof the total film weight.
 6. The film according to claim 3, whereindexmedetomidine hydrochloride is present at about 0.1% to about 0.2% w/wof the total film weight, hydroxypropyl cellulose having a molecularweight of about 40,000 daltons is present at about 5% w/w of the totalfilm weight; and hydroxypropyl cellulose having a molecular weight ofabout 140,000 daltons is present at about 5% w/w of the total filmweight.
 7. The film according to claim 3, wherein the composition ofpart (a) comprises a colorant and the film substrate of part (b)comprises a colorant, wherein the colorant in part (a) is a differentcolor from the colorant in part (b).
 8. The film according to claim 3,wherein the composition of part (a) covers a portion of the surface ofthe film substrate of part (b).
 9. The film according to claim 1,wherein the film has a thickness of about 20 micrometers to about 200micrometers.
 10. The film according to claim 1, wherein the film has athickness of about 20 micrometers to about 200 micrometers and covers anarea (width×length) of about 100 mm² to about 300 mm².
 11. The filmaccording to claim 1, wherein the film has a disintegration time ofabout 60 seconds to about 180 seconds.
 12. The film according to claim1, wherein the film has a mucoadhesion force of about 1000 g to about2000 g.
 13. The film according to claim 1, wherein said dexmedetomidineor a pharmaceutically acceptable salt thereof is present in an amount ofabout 10 micrograms.
 14. The film according to claim 1, wherein saiddexmedetomidine or a pharmaceutically acceptable salt thereof is presentin an amount of about 20 micrograms.
 15. The film according to claim 1,wherein said dexmedetomidine or a pharmaceutically acceptable saltthereof is present in an amount of about 30 micrograms.
 16. The filmaccording to claim 1, wherein said dexmedetomidine or a pharmaceuticallyacceptable salt thereof is present in an amount of about 40 micrograms.17. The film according to claim 1, wherein said dexmedetomidine or apharmaceutically acceptable salt thereof is present in an amount ofabout 60 micrograms.
 18. A method of treating agitation in a subjectcomprising administering buccally to the agitated subject a filmaccording to claim
 1. 19. The film according to claim 1, wherein thefilm is completely dissolvable in oral mucosal fluid in about 1 minuteto about 5 minutes.
 20. The film according to claim 1, wherein saiddexmedetomidine or a pharmaceutically acceptable salt thereof is presentin an amount of about 90 micrograms.
 21. The film according to claim 1,wherein said dexmedetomidine or a pharmaceutically acceptable saltthereof is present in an amount of about 120 micrograms.
 22. The filmaccording to claim 1, wherein said film is administered in one or moreunits to provide a total daily dose of dexmedetomidine or apharmaceutically acceptable salt thereof of about 120 micrograms. 23.The film according to claim 1, wherein said film is administered in oneor more units to provide a total daily dose of dexmedetomidine or apharmaceutically acceptable salt thereof of about 180 micrograms. 24.The film according to claim 3, wherein said film is administered in oneor more units to provide a total daily dose of dexmedetomidinehydrochloride of about 120 micrograms.
 25. The film according to claim3, wherein said film is administered in one or more units to provide atotal daily dose of dexmedetomidine hydrochloride of about 180micrograms.
 26. The film according to claim 1, wherein dexmedetomidineor a pharmaceutically acceptable salt thereof is present on one surfaceof said film substrate and covers a portion of the surface of said filmsubstrate at more than one isolated surface locations.
 27. The filmaccording to claim 3, wherein said composition of part (a) is present onthe surface of the film substrate (b) and covers a portion of thesurface of said film substrate at more than one isolated surfacelocations.